TW200412967A - Novel imidazopyrazines as cyclin dependent kinase inhibitors - Google Patents

Novel imidazopyrazines as cyclin dependent kinase inhibitors Download PDF

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TW200412967A
TW200412967A TW092125931A TW92125931A TW200412967A TW 200412967 A TW200412967 A TW 200412967A TW 092125931 A TW092125931 A TW 092125931A TW 92125931 A TW92125931 A TW 92125931A TW 200412967 A TW200412967 A TW 200412967A
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Kamil Paruch
Timothy J Guzi
Michael P Dwyer
Ronald J Doll
Viyyoor M Girijavallabhan
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Schering Corp
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

In its many embodiments, the present invention provides a novel class of imidazo[1,2-a]pyrazine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

Description

200412967 玖、發明說明： 【發明所屬之技術領域】 本發明係關於用作蛋白激酶抑制劑（如例如週期素依賴性 激酶抑制劑、以促細胞***劑活化之蛋白激酶（mapk/erk) 、糠原合成酶激酶3 (GSK3P)及類似物）之咪唑并n,2-a]吡嗪 化^物、包括化合物之醫藥組合物以及使用化合物和組: 物治療疾病的方法，如例如癌症、發炎、關節炎、病毒疾 届、神經變性疾病（如阿茲海默氏病）、心血管疾病及霉菌 陡疾病义類的疾病。本申請案比在2002年9月23日提出申請 <美國臨時申請序案第60/412,906號優先提出。 【先前技術】 蛋白激酶抑制劑包括如例如週期素依賴性激酶抑制劑 (CDK)、以促細胞***劑活化之蛋白激酶（MAPK/ERK)、糖 原合成酶激酶3 (GSK3P)及類似物之類的激酶。週期素依賴 ^激鉍係絲胺酸/蘇胺酸蛋白激酶，其係在細胞循環及細胞 曰〈後的起動力。個別的CDK(如CDK1、CDK2、CDfG、 CDK4、CDK5、CDK6和CDK7、CDK8及類似物）在細胞循環進 度中執仃不同的角色，並可以分類成或Gl、S或G2M相酵素 不文控制的增殖作用係癌症細胞的標記，並在許多重要 、口把腫瘤中經常發生不規則的Cdk機能。CDK2及CDK4具 =特刈的利害關係，因為彼等在各種廣泛的人類癌症中常 “有不規則的活性。CDK2活性係經由細胞循環的G丨進展至 太斤必要的，以及CDK2係G1檢查點的重要組成之一。檢 一 4具有維持適當的細胞循環事件的序列及允許細胞回應 87870 200412967 傷害或增殖信號，而且喪失在癌症細胞中適當的檢查點控 制會助長腫瘤生成作用。CDK2路徑會影響腫瘤抑制機能 (例如，p52、RB及p27)及致癌基因活化（週期素E)程度的腫 瘤生成作用。許多報告已證明輔助活化劑，週期素E及 CDK2之抑制劑（p27)兩者分別在乳癌、直腸癌、非小細胞肺 癌、胃癌、攝護腺癌、膀胱癌、非何杰金氏淋巴瘤（non-200412967 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to the use as protein kinase inhibitors (such as, for example, cyclin-dependent kinase inhibitors, protein kinases (mapk / erk) activated by mitogens, bran Prosynthase kinase 3 (GSK3P) and the like), imidazon, 2-a] pyrazinates, pharmaceutical compositions including the compounds, and methods of using the compounds and groups to treat diseases such as, for example, cancer, inflammation , Arthritis, viral disease, neurodegenerative diseases (such as Alzheimer's disease), cardiovascular diseases and mildew diseases. This application has priority over the application filed on September 23, 2002 < US Provisional Application No. 60 / 412,906. [Prior art] Protein kinase inhibitors include, for example, cyclin-dependent kinase inhibitors (CDK), mitogen-activated protein kinases (MAPK / ERK), glycogen synthase kinase 3 (GSK3P), and the like Class of kinases. Cyclin-dependent bismuth-based serine / threonine protein kinase, which is the starting motive force in the cell cycle and cells. Individual CDKs (such as CDK1, CDK2, CDfG, CDK4, CDK5, CDK6 and CDK7, CDK8, and the like) perform different roles in the progress of the cell cycle and can be classified into G1, S, or G2M phase enzymes that are not controlled by the text Proliferative effects are markers of cancer cells, and irregular Cdk function often occurs in many important, oral tumors. CDK2 and CDK4 have a special interest because they often "have irregular activities in a wide variety of human cancers. CDK2 activity is necessary to progress to too much weight through the G of the cell cycle, and CDK2 is a G1 checkpoint One of the important components of the test. ZY-4 has a sequence that maintains proper cell cycle events and allows cells to respond to 87870 200412967 injury or proliferation signals, and the loss of proper checkpoint control in cancer cells will promote tumorigenesis. The CDK2 pathway will affect Tumor suppressive effects (eg, p52, RB, and p27) and tumorigenicity of the level of oncogene activation (cyclin E). Many reports have demonstrated that auxiliary activators, inhibitors of cyclin E and CDK2 (p27) are in Breast cancer, rectal cancer, non-small cell lung cancer, stomach cancer, prostate cancer, bladder cancer, non-Hodgkin's lymphoma (non-

Hodgkin’s) 、 卵巢癌及其 它癌症 中或過度表現 或表現 不足。 已證明彼等不同的表現與增加的CDK2活性值及差的總存活 率有相互的關係。該觀察係以CDK2及其調整路徑為多年發 展的強制標的，已在文獻中提出以許多腺苷5-三磷酸（ATP) 競爭性小有機分子與肽作為有效的癌症治療的CDK抑制劑 。美國專利第6,413,974號第1段第23行至第15段第10行提供 各種CDK的完整說明及彼等與各種癌症型式的相互關係。 已知CDK抑制劑。例如，氟維皮瑞多（flavopiridol)(式I)係 目前正在進行人類臨床試驗的非選擇性CDK抑制劑，A. M. 山德若威茲（Sanderowicz)等人之 J. Clin. Oncol· (1998) 16, 2986-2999。 ch3Hodgkin ’s), ovarian cancer, and other cancers are either over- or under-expressed. Their different manifestations have been shown to correlate with increased CDK2 activity values and poor overall survival rates. This observation is based on CDK2 and its regulatory pathway as a mandatory target for many years of development. Many adenosine 5-triphosphate (ATP) competitive small organic molecules and peptides have been proposed in the literature as effective CDK inhibitors for cancer treatment. U.S. Patent No. 6,413,974, paragraph 1, line 23 to paragraph 15, line 10 provides a complete description of the various CDKs and their correlation with various cancer types. CDK inhibitors are known. For example, flavipiridol (formula I) is a non-selective CDK inhibitor currently undergoing human clinical trials, J. Clin. Oncol, AM Sanderowicz et al. (1998) 16, 2986-2999. ch3

其它已知的CDK抑制劑包括例如歐羅茂辛（olomoucine)( J.維 200412967 斯理（Vesely)等人之 Eur. J_ Biochem.，（1994) 224? 771-786)及若斯可 維提（roscovitine)(I·梅傑爾（Meijer)等人之 Eur. J. Biochem.，（1997) Ml，527-536)。U.S. 6，107,305說明作為CDK抑制劑特定的吡唑并 [3,4-b]吡啶化合物。所有以’305專利例證的化合物具有式II :Other known CDK inhibitors include, for example, olomoucine (J. Victoria 200412967 Vesely et al. Eur. J_Biochem., (1994) 224? 771-786) and roscovitine ) (I. Meijer et al. Eur. J. Biochem., (1997) Ml, 527-536). U.S. 6,107,305 illustrates pyrazolo [3,4-b] pyridine compounds specific as CDK inhibitors. All compounds exemplified by the '305 patent have formula II:

K· S.金姆（Kim)等人之 J. Med· Chem· (2002) 3905-3927及 WO 02/10162揭示作為CDK抑制劑特定的胺基噻唑化合物。J. Med. Chem. (2002) 3905-3927 and WO 02/10162 by K.S. Kim et al. Disclose specific aminothiazole compounds as CDK inhibitors.

已知吡唑并嘧啶。例如，WO92/18504、W002/50079、W095/35298 、W002/40485、EP94304104.6、EP0628559(相當於美國專利第 5,602，136 號、第 5,602，137 號及第 5,571，813 號）、U_S. 6,383,790、Chem. Pharm. Bull·，（1999) 42 928、J· Med. Chem.，（1977)並，296、J. Med. Chem·， (1976) 19 517 及 Chem. Pharm· Bull·，（1962) 10 620 揭示各種 p比吐并口密 淀。 對用於治療與CDK有關連之疾病及異常的新化合物、調 配物、治療及治療法有需求。因此本發明的目的係提供在 治療或預防或改善這些疾病及異常有用的化合物。 【發明内容】 在本發明的許多具體實施例中，其係提供一種作為週期 87870 200412967 ^# #i ^ ^c i,2'a] "k ^ 'b"^ ^ ^ ^ ^ 、，绝1化合物的方法、包含一或多種這些化合物之g, 藥組合物、製備含有一或多種這些化合物之醫藥調配物： 万法、以及使用這些化合物或醫藥組合物治療、預防、抑 制或改善一或多種與CDK有關連之疾病的方法。 在本發明的一個觀點中，其係揭示一種化合物或該化八 物在I藥上可接受之鹽類或媒合物，該化合物具有以式I 所示之通式結構··Pyrazolopyrimidines are known. For example, WO92 / 18504, W002 / 50079, W095 / 35298, W002 / 40485, EP94304104.6, EP0628559 (equivalent to US Patent Nos. 5,602,136, 5,602,137, and 5,571,813), U_S. 6,383,790 Chem. Pharm. Bull., (1999) 42 928, J. Med. Chem., (1977) and 296, J. Med. Chem., (1976) 19 517, and Chem. Pharm. Bull., (1962 ) 10 620 Reveals various p ratios. There is a need for new compounds, formulations, treatments and therapies for the treatment of diseases and abnormalities associated with CDK. It is therefore an object of the present invention to provide compounds useful in the treatment or prevention or amelioration of these diseases and abnormalities. [Summary of the Invention] In many specific embodiments of the present invention, it provides a cycle 87870 200412967 ^ # #i ^ ^ ci, 2'a] " k ^ 'b " ^ ^ ^ ^ ^, absolutely 1 Methods of compounds, pharmaceutical compositions containing one or more of these compounds, pharmaceutical compositions, preparation of pharmaceutical formulations containing one or more of these compounds: Wanfa, and use of these compounds or pharmaceutical compositions to treat, prevent, inhibit or ameliorate one or more Methods for CDK-related diseases. In one aspect of the present invention, it is disclosed that a compound or a compound or a compound thereof is a pharmaceutically acceptable salt or vehicle of the compound I, and the compound has a general structure represented by Formula I ...

式III 其中： R係選自由烷基、CF3、雜芳基、雜芳烷基、環烷基、環 燒基燒基基、雜環烷基、芳烷基、_C(〇)R7、Formula III wherein: R is selected from the group consisting of alkyl, CF3, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkyl, heterocycloalkyl, aralkyl, -C (〇) R7,

N\ \N \ \

及 所組成的群組，其中每一個該烷基、雜芳基、芳烷基、環 火元基、雜5衣基及雜壤基部份其結構係如以上剛以R所示者 可以未經取代或視需要獨立以一或多個可以相同或不相同 的邵份取代，每一部份係獨立選自由画素、烷基、環境式 87870 200412967 、CF3、CN、-〇CF3、-OR6、-C(〇)R7、-NR5R6、-C(〇2)R6、-C(〇)NR5R6 、-(Cm5)nOR6、-SR6、_S(〇2)r7、-S(〇2輝5R6、-N(R5)S(〇2)R7、 -N(R5)C(〇)R7及-N(R5)C(〇)NR5R6所組成的群組； R1係Η、li素或燒基； R2係選自由Η、鹵素、CN、環烷基、雜環基、炔基及-CF3 所組成的群組； R3係選自由芳基（除了苯基之外）、雜芳基（除了呋喃基之 外）、雜環基、-(CHR5)n-雜芳基、-S(〇2)R6、-C(〇)R6、-S(〇2)NR5R6 -(CHR5)n—n^\ , ς -(CHR5)n—N Vr8 、-C(0)〇R6、-c(〇)nr5r6、 〇 ，、 \_y :及 r(CH2)m^R8 所組成的群組，其中每一個該芳基、雜芳 基及雜環基可以未經取代或視需要以一或多個可以相同或 不相同的邵份取代’每一邵份係獨立選自由鹵素、、J：充基、 芳基、環烷基、CF3、CN、-OCF3、-OR5、-NR5R6、-C(02)R5、 -c(o)nr5r6、-SR6、-s(〇2)r6、-s(〇2)nr5r6、-n(r5)s(o2)r7、-n(r5)c(o)r7 及-N(R5)C(0)NR5R6所組成的群組’其先決條件係當R3係 -(CHR5)n-雜芳基時，貝|J R2可以另夕卜係燒基； R5係Η或烷基； R6係選自由Η、烷基、芳基、雜芳基、芳烷基及雜芳烷 基所組成的群組，其中每一個該烷基、雜芳烷基、芳基、 雜芳基及芳烷基可以未經取代或視需要以一或多個可以相 同或不相同的部份取代，每一部份係獨立選自由鹵素、：!：完 基、芳基、環烷基、CF3、〇CF3、CN、-OR5、-NR5R6、-CH2〇R5、 -c(o2)r5、-c(o)nr5r6、-SR6、-s(02)r7、-s(02)nr5r6、-n(r5)s(o2)r7 87870 -10- 200412967 、-N(R5)C(〇)R7 及-n(r5)c(o)nr5r6 所組成的群組； R7係選自由烷基、芳基 '雜芳基、芳烷基及雜芳烷基所 組成的群組，其中每一個該烷基、雜芳烷基、芳基、雜芳 基及芳烷基可以未經取代或視需要以一或多個可以相同或 不相同的邵份取代’每一部份係獨立選自由鹵素、燒基、 芳基、環烷基、CF3、OCF3、CN、-〇R5、-NR5R6、-CH2OR5、 -C(〇2)R)、-C(0)NR5R6、-SR6、-s(o2)r7、-S(02)NR5R6、-n(r5)s(〇2)r7 、-n(r5)c(o)r7 及-n(r5)c(〇)nr5r6所組成的群組； R8 係選自由 R6、-C(〇)NR5R6、-S(〇2)NR5R6、-C(0)R7、-C(〇2)R6、 _s(〇2)r7及—(cHy-芳基所組成的群組； m係0至4 ;及 η係 1-4 。 可將式III化合物用作蛋白激酶抑制劑，並可用於治療及 預防增殖性疾病，例如，癌症、發炎及關節炎。也可用於And the group consisting of each of the alkyl, heteroaryl, aralkyl, cyclophosphine, heteroquinyl and heterophosphyl groups whose structures are as shown above by R Substituted or independently substituted with one or more of the same or different, if necessary, each part is independently selected from the group consisting of pixels, alkyl, environmental formula 87870 200412967, CF3, CN, -〇CF3, -OR6, -C (〇) R7, -NR5R6, -C (〇2) R6, -C (〇) NR5R6,-(Cm5) nOR6, -SR6, _S (〇2) r7, -S (〇2 辉 5R6,- A group consisting of N (R5) S (〇2) R7, -N (R5) C (〇) R7, and -N (R5) C (〇) NR5R6; R1 is fluorene, lidin, or alkyl; R2 is Selected from the group consisting of fluorene, halogen, CN, cycloalkyl, heterocyclyl, alkynyl, and -CF3; R3 is selected from aryl (other than phenyl), heteroaryl (other than furanyl) ), Heterocyclyl,-(CHR5) n-heteroaryl, -S (〇2) R6, -C (〇) R6, -S (〇2) NR5R6-(CHR5) n-n ^ \, ς- (CHR5) n-N Vr8, -C (0) 〇R6, -c (〇) nr5r6, 〇, \ _y: and r (CH2) m ^ R8, each of which is an aryl group, Heteroaryl and heterocyclyl can be unsubstituted Substitute one or more of the same or different components as necessary. Each component is independently selected from the group consisting of halogen, J: charge group, aryl, cycloalkyl, CF3, CN, -OCF3, -OR5, -NR5R6, -C (02) R5, -c (o) nr5r6, -SR6, -s (〇2) r6, -s (〇2) nr5r6, -n (r5) s (o2) r7, -n ( r5) c (o) r7 and -N (R5) C (0) NR5R6's prerequisite is that when R3 is-(CHR5) n-heteroaryl, J | R2 can be different R5 is fluorene or alkyl; R6 is selected from the group consisting of fluorene, alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is alkyl, heteroaryl Alkyl, aryl, heteroaryl and aralkyl can be unsubstituted or optionally substituted with one or more moieties which may be the same or different, and each moiety is independently selected from halogen,:!: , Aryl, cycloalkyl, CF3, 〇CF3, CN, -OR5, -NR5R6, -CH2〇R5, -c (o2) r5, -c (o) nr5r6, -SR6, -s (02) r7, -s (02) nr5r6, -n (r5) s (o2) r7 87870 -10- 200412967, -N (R5) C (〇) R7 and -n (r5) c (o) nr5r6; R7 is selected from the group consisting of alkyl, aryl'heteroaryl, arane And heteroaralkyl groups, each of which may be unsubstituted or one or more may be the same or different as needed Each part of the substituent is independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -CH2OR5, -C (〇2) R), -C (0) NR5R6, -SR6, -s (o2) r7, -S (02) NR5R6, -n (r5) s (〇2) r7, -n (r5) c (o) r7, and -n ( r5) c (〇) nr5r6; R8 is selected from R6, -C (〇) NR5R6, -S (〇2) NR5R6, -C (0) R7, -C (〇2) R6, _s A group consisting of r7 and-(cHy-aryl; m is 0 to 4; and n is 1-4. Compounds of formula III can be used as protein kinase inhibitors and can be used to treat and prevent proliferative diseases such as cancer, inflammation and arthritis. Can also be used

疾病及霉菌性疾病。 【實施方式】 在本發明的-個具體實施例中，其係揭示以結構式ΙΠ代 表的咪唑并[Ha]吡嗪化合物、其在醫藥上可接受之鹽或媒 a物’其中各種部份係如以上所述。 在較佳的具體實施例中 環故基、環烷基烷基、雜: 丨中’ R係選自由虎基、雜芳垸基、 雜環基、雜環烷基 '芳烷基、 87870 200412967Diseases and fungal diseases. [Embodiment] In a specific embodiment of the present invention, it discloses various parts of the imidazo [Ha] pyrazine compound represented by the structural formula II and its pharmaceutically acceptable salt or vehicle. It is as described above. In a preferred embodiment, the cycloalkyl, cycloalkylalkyl, and hetero: R ′ is selected from the group consisting of tigeryl, heteroarylfluorenyl, heterocyclyl, heterocycloalkyl, aralkyl, 87870 200412967

所組成的群組，其中以上R所示之每一個該烷基、雜芳基 、環烷基、芳烷基、雜環基及雜環基部份可以未經取代^ 視需要獨立以一或多個可以相同或不相同的部份取代，每 一部份係獨立選自由画素、烷基、環烷基、CF3、cn'_〇ci^ 、-OR6、_C(0)R7、-NR)r6、_C(〇2)r6、-(：(〇輝5116、_sr6、_s(〇2)r7、 名(〇2輝卞6、_N(R5)S(〇2)R7、-N(R5)C(0)R7 及-N(R5)C(〇娜 成的群組； 在另一個較佳的具體實施例中，Ri係H或鹵素。 在另一個較佳的具體實施例中，R2係選自由Η、鹵素、 環燒基、CN、炔基及_CF3所組成的群組。 在另一個較佳的具體實施例中，R3係選自由芳基、雜芳 基、雜環基、_(CHR5)n-雜芳基、-S(02)R6、-C(0)R6、-S(02)NR5R6 、-c(〇)〇R6、-c(o)nr5r6 、/(CH2)nA group consisting of each of the alkyl, heteroaryl, cycloalkyl, aralkyl, heterocyclyl, and heterocyclyl moieties shown by R above may be unsubstituted ^ independently as necessary Multiple may be the same or different parts, each part is independently selected from the group consisting of pixels, alkyl, cycloalkyl, CF3, cn'_〇ci ^, -OR6, _C (0) R7, -NR) r6, _C (〇2) r6,-(: (〇 辉 5116, _sr6, _s (〇2) r7, name (〇2 辉 卞 6, _N (R5) S (〇2) R7, -N (R5) C (0) R7 and -N (R5) C (〇Na group; in another preferred embodiment, Ri is H or halogen. In another preferred embodiment, R2 is Is selected from the group consisting of fluorene, halogen, cycloalkyl, CN, alkynyl and _CF3. In another preferred embodiment, R3 is selected from the group consisting of aryl, heteroaryl, heterocyclyl, _ (CHR5) n-heteroaryl, -S (02) R6, -C (0) R6, -S (02) NR5R6, -c (〇) 〇6, -c (o) nr5r6, / (CH2) n

-(CHR5)n——N-(CHR5) n——N

-(CHR5)n.-(CHR5) n.

-N N—R8 所組成的群組，其中每一個該芳基、雜芳 基及雜環基可以未經取代或視需要以一或多個可以相同或 不相同的部份取代，每一部份係獨立選自由鹵素、烷基、 芳基、環烷基、CF3、CN、-0CF3、-N(R5)C(〇)R7、-C(〇)NR)R6、 87870 -12 - 200412967 -S(〇2)R6及-N(R5)C(〇)R7所組成的群組。 在另一個較佳的具體實施例中，R5係Η或低碳烷基。 在另一個較佳的具體實施例中，m係0至2。 在另一個較佳的具體實施例中，η係1至3。 在額外較佳的具體實施例中，r係選自由甲基、乙基、 三級-丁基、環己基甲基、芊基及苯乙基所組成的群組。 在額外較佳的具體實施例中，R1係Η、Βι*或甲基。 在額外較佳的具體實施例中，R2係F、ci、Br、I、環己 基或CF3。 在額外較佳的具體實施例中，R3係（吡啶-2_基）甲基、（吡 呢-3-基）甲基、（吡啶_4_基）甲基、噻嗯基或噻嗯_3-基， 其中該吡啶基或噻嗯基可以未經取代或視需要以一或多個 可以相同或不相同的部份取代，每一部份係獨立選自由F、 Cl、Br、CF3、低碳烷基、.甲氧基及CN所組成的群組。 在額外較佳的具體實施例中，R5係Η。 在額外較佳的具體實施例中，〇。 在額外較佳的具體實施例中，η係1或2。 將本發明較佳的化合物群組展示在表1中。 87870 13 200412967 表1-NN—R8, wherein each of the aryl, heteroaryl, and heterocyclic groups may be unsubstituted or substituted with one or more moieties which may be the same or different, as required Is independently selected from halogen, alkyl, aryl, cycloalkyl, CF3, CN, -0CF3, -N (R5) C (〇) R7, -C (〇) NR) R6, 87870 -12-200412967 -S (02) a group consisting of R6 and -N (R5) C (〇) R7. In another preferred embodiment, R5 is fluorene or lower alkyl. In another preferred embodiment, m is 0 to 2. In another preferred embodiment, n is 1 to 3. In a further preferred embodiment, r is selected from the group consisting of methyl, ethyl, tertiary-butyl, cyclohexylmethyl, fluorenyl and phenethyl. In additional preferred embodiments, R1 is fluorene, Bi * or methyl. In additional preferred embodiments, R2 is F, ci, Br, I, cyclohexyl or CF3. In additional preferred embodiments, R3 is (pyridin-2-yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, thienyl or thienyl 3-yl, wherein the pyridyl or thionyl may be unsubstituted or optionally substituted with one or more moieties which may be the same or different, each moiety being independently selected from the group consisting of F, Cl, Br, CF3, A group of lower alkyl, .methoxy, and CN. In an additional preferred embodiment, R5 is rhenium. In an additional preferred embodiment, 0. In an additional preferred embodiment, n is 1 or 2. The preferred compound groups of the present invention are shown in Table 1. 87870 13 200412967 Table 1

應瞭解的是如本文及在整個揭示内容所使用的以下術^五 具有以下的意義，除非有其它另外的指定： 以“病患，，同時包括人類及動物。 以‘哺乳類”代表人類及其它哺乳類動物。 以烷基”代表可以係直鏈或支鏈及包含約丨至約2〇個在鏈 中的碳原子之脂肪族烴基。較佳的烷基包括約丨至約12個在 鏈中的碳原子。更佳的烷基包括約丨至約6個在鏈中的碳原 子^支鏈代表以一或多個低碳烷基（如〒基、乙基或丙 土）附接A直鏈烷基。以“低碳烷基，，代表具有約1至約6個在 鏈中的碳；# ” 人屌于炙基，其可以係直鏈或支鏈。以“經取代之烷 斤口代表可將烷基以一或多個可以相同或不相同的取代 87870 -14- 200412967 基取代，每一個取代基係獨立選自由商基、燒基、芳基、 環燒基、氰基、幾基、燒氧基、燒硫基、胺基、-卿完幻 、刪環垸基）、-N(燒基）2、叛基及_c(〇)〇_燒基所組成的群 組。適合嶋的非限制性實例包括甲基、乙基、正丙基 、異丙基及三級-丁基。 以“块基，，代表包括至少—個碳-碳參鍵和其可以係直鏈或 支鏈及包含約2至約15個在鏈中的碳原子之脂防族烴基。較 佳的块基具有約2至約12個在鏈中的碳原子，並以約2至約4 個在鏈中的碳原子更佳。、义古料 > 主 丁文住以支鏈代表以一或多個低碳烷基 (如甲基、乙基或丙基）附接於直鏈炔基。以“低碳块基”代 表約2至約6個在鏈中的碳原子，其可以係直鏈或支鍵。適 合的块基的非限制性實例包括乙块基、丙块基、2_ 丁块基 :3二基丁块基。以“經取代之块基，，術語代表可將炔基以 -或多個可以相同或不相同的取代基取代，每—個取代基 係獨立選自由垸基、芳基及魏基所組成的群組。 :“芳基”代表含有約6至約14個碳原子之芳族單環或多環 ^系統’以約6至約職碳原子較佳。可將芳基視需要以 或多個可以相同或不相同及如本文定義之“環系統取代 土取代。通合的芳基的非限制性實例包括苯基及关基。 以“雜芳基，，代表含有約5至約14個環原子之芳族單環或多 :衣系環系統’以約5至約10個環原子較佳，其中一或多個環 访子:系:了碳之外的元素’例如’單獨或组合的氮、氧或 的雜芳基包括約5至約6個環原子。可將“雜芳基，， ’“要以一或多個可以相同或不相同及如本文定義之“環系 87870 200412967 統取代基”取代。在雜芳基根命名之前附加的氮雜、氧雜或 硫雜分別代表至少一個氮、氧或硫原子以環原子存在。可 將雜方基的氮原子視需要氧化成對應之N_氧化物。適合的 雜芳基的非限制性實例包括吡啶基、吡嗪基、呋喃基、。塞 嗯基、嘧啶基、吡啶酮（包括以队取代之吡啶酮）、異噁唑 基、異4唑基、噁唑基”塞唑基、吡唑基、呋咱基、吡咯 基说坐基一唑基、1，2,4^塞二唑基、吡嗪基、噠嗪基、 喹噁啉基、酞嗪基、羥吲哚基、咪唑并[Ha]吡啶基、咪唑 并[2，i-bM吐基、苯并吱咱基、吲哚基、氮雜⑷哚基、苯并 咪唑基、料嘍嗯基' 喹啉基、咪唑基”塞嗯并吡啶基、 喳唑啉基、噻嗯并嘧啶基 '吡咯并吡啶基、咪唑并吡啶基 、異峻琳基、苯并氮雜P㈣基、u，心三嗪基、苯并。塞峻基 及類似物。“雜芳基，，術語也表示部份飽和雜芳基部份，如 例如四氫異喹啉基、四氫喹啉基及類似物。 以万：基或‘方基烷基”代表其中芳基及烷基係如先前 斤id之芳基烷基。較佳的芳烷基包含低碳烷基。適合的芳 垸基的非限制性實例包料H苯乙基及莕甲基。與母 體邵份係經由燒基結合。 〜以烷基万基代表其中烷基及芳基係如先前所述之烷基_ 万基較佳的烷基芳基包含低碳烷基。適合的烷基芳基的 非限制性貫例包括甲苯基。與母體部份係、經由芳基結合。 以％烷基代表含有約3至約10個碳原子之非芳族單-或 ^環系環系統，以約5至約1〇個碳原子較佳。較佳的環烷基 衣G括、5 土約7個％原子。可將環烷基視需要以一或多個 87870 -16- 200412967 、1，不相周及如本文定義之“環系統取代基，，取代。適合 、單衣系％烷基的非限制性實例包括環丙基、環戊基、環 i 土銥庚基及類似物。適合的多環系環烷基的非限制性 …例匕括1-奈烷基、降冰片烷基、金鋼烷基及類似物與部 份飽和物# ’如例如莽職、四氫審基及類似物。 以‘‘南素，，代表氟、氯、溴或碘。 、以“環系統取代基，，代表附接於芳族或非芳族環系統之取 代基，以其例如置換在環I统上可用的氫。環系統取代基 可以：同或不相同，每一個係獨立選自由烷基、烯基、块 基、芳基、雜芳基、芳燒基、垸基芳基、雜芳燒基、雜芳 ，基、雜芳块基、㉟基雜芳基、輕基、㈣基、垸氧基、 芳氧基、芳燒氧基、醯基、芳醯基、齒基、確基、氯芙、 幾基/氧基錢、純錢基、㈣氧基羰基ϋ酿 基、芳磺醯基、雜芳磺醯基、烷硫基、芳硫基、雜芳硫基 、芳烷硫基、雜芳烷硫基、環烷基、雜環基、-CPN-CN) 、顺2、<(=顺)-腿2、戊基）、m γ&Ν 烷基、YiY2NC(〇)-、YiY2NS02-及-S〇2NYiY2，其中 Υι 及 可2广 相同或不相同，並係獨立選自由笱、栌I _甘 2 、 ^ 砭基、方基、環烷基 及芳燒基所組成的群組。“環系統取代基，，4 L j以代表同時 置換在環系統上兩個鄰接的碳原子上的兩個可用的氫 碳上一個氫）之單一部份。該部份的實例係甲二氧美 氧撐、-C(CH3)r及類似物，其形成如例如·· 土 —It should be understood that the following techniques, as used herein and throughout the disclosure, have the following meanings, unless otherwise specified: "Patients, including both humans and animals." Humans "and others Mammals. "Alkyl" represents an aliphatic hydrocarbon group which may be straight or branched and contains from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups include about 1 to about 12 carbon atoms in the chain Better alkyl groups include about 1 to about 6 carbon atoms in the chain ^ Branched chains represent A linear alkyl groups attached to one or more lower carbon alkyl groups (such as fluorenyl, ethyl, or propionite) . With "lower alkyl," which has about 1 to about 6 carbons in the chain; "", which is a straight or branched chain. "Substituted alkane represents The alkyl group is substituted with one or more substituents which may be the same or different. 87870 -14- 200412967, each substituent is independently selected from the group consisting of a commercial group, an alkyl group, an aryl group, a cycloalkyl group, a cyano group, a few groups, A group consisting of an alkoxy group, an thio group, an amine group, -Qing Wanhuan, a cyclohexyl group), -N (an alkynyl group) 2, a renyl group, and a _c (〇) 〇_ group. Non-limiting examples of suitable hydrazones include methyl, ethyl, n-propyl, isopropyl, and tertiary-butyl. "Block group" represents an aliphatic hydrocarbon group comprising at least one carbon-carbon reference bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms in the chain. A preferred block group It has about 2 to about 12 carbon atoms in the chain, and more preferably about 2 to about 4 carbon atoms in the chain. A lower alkyl group (such as methyl, ethyl, or propyl) is attached to a straight chain alkynyl group. The term "lower carbon block group" represents about 2 to about 6 carbon atoms in the chain, which may be a straight chain or Branches. Non-limiting examples of suitable blocks include ethyl block, propyl block, 2-butyl block: 3-dibutyl block. With "substituted block group," the term means that the alkynyl group can be replaced by- Multiple or more may be substituted with the same or different substituents, and each substituent is independently selected from the group consisting of a fluorenyl group, an aryl group, and a weyl group. "Aryl" represents an aromatic monocyclic or polycyclic ring system containing from about 6 to about 14 carbon atoms, and preferably from about 6 to about carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituted soils which may be the same or different and as defined herein. Non-limiting examples of aryl groups include phenyl and guanyl. With" heteroaryl, , Represents an aromatic monocyclic ring or multiples containing about 5 to about 14 ring atoms: a ring system of clothing is preferably about 5 to about 10 ring atoms, of which one or more ring visitors: Department: the carbon The external elements, for example, nitrogen, oxygen or heteroaryl, alone or in combination, include about 5 to about 6 ring atoms. "Heteroaryl" may be substituted with one or more "ring system 87870 200412967 system substituents" which may be the same or different and are as defined herein. The aza, oxa or thia added before the heteroaryl root name represents that at least one nitrogen, oxygen or sulfur atom respectively exists as a ring atom. The nitrogen atom of the heterosquaryl group can be optionally oxidized to the corresponding N_oxide. Non-limiting examples of suitable heteroaryl groups include pyridyl, pyrazinyl, furyl, and the like. Cymenyl, pyrimidinyl, pyridone (including pyridone substituted with a team), isoxazolyl, isoxazolyl, oxazolyl "sedazolyl, pyrazolyl, furoxanyl, pyrrolyl Monozolyl, 1,2,4 ^ diadiazolyl, pyrazinyl, pyridazinyl, quinoxaline, phthalazinyl, oxindolinyl, imidazo [Ha] pyridyl, imidazo [2, i-bM thiol, benzyl, indolyl, azapyridyl, benzimidazolyl, pyrimyl 'quinolinyl, imidazolyl, thienylpyridyl, oxazoline, Thiopyrimidinyl'pyrrolopyridyl, imidazopyridyl, isojunyl, benzoazapyridinyl, u, cardiac triazinyl, benzo. Se Junji and the like. "Heteroaryl", the term also refers to partially saturated heteroaryl moieties, such as, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and the like. The term "aryl:" or "square alkyl" refers to aryl The radicals and alkyl radicals are the same as the arylalkyl radicals. Preferred aralkyls include lower alkyl. Non-limiting examples of suitable arylfluorenyl groups include Hphenethyl and fluorenylmethyl. It is bonded to the parent shao group via a base. ~ The alkyl aryl group is represented by the alkyl aryl group in which the alkyl group and the aryl group are as described above. The preferable alkyl aryl group includes a lower alkyl group. Non-limiting examples of suitable alkylaryl groups include tolyl. It is bound to the parent moiety through an aryl group. Non-aromatic mono- or tricyclic ring systems containing from about 3 to about 10 carbon atoms are represented by% alkyl, preferably from about 5 to about 10 carbon atoms. The preferred cycloalkyl group G is 5 to about 7 atom%. Cycloalkyl can be optionally substituted with one or more 87870-16-200412967, 1, not as relevant, and "ring system substituents," as defined herein. Non-limiting examples of suitable, uncoated% alkyl groups include cyclopropyl Base, cyclopentyl, cyclic iridium heptyl, and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups ... Examples include 1-naphthyl, norbornyl, auryl and the like With partial saturates # 'such as, for example, hydrogen, tetrahydrobenzyl, and the like. The term “nanin” represents fluorine, chlorine, bromine, or iodine, and the “ring system substituent” represents attachment to aromatic compounds. Group or non-aromatic ring system substituents, for example, to replace the hydrogen available on the ring system. The ring system substituents may be the same or different, each of which is independently selected from the group consisting of alkyl, alkenyl, block, aryl, heteroaryl, aryl, fluorenylaryl, heteroaryl, heteroaryl, Group, heteroaryl block group, fluorenyl heteroaryl group, light group, fluorenyl group, fluorenyl group, aryloxy group, aryloxy group, fluorenyl group, aryl fluorenyl group, dentyl group, acyl group, chlorophene, and several groups / Oxyalkyl, pure alkyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio Group, cycloalkyl, heterocyclyl, -CPN-CN), cis2, < (= cis) -leg2, pentyl), m γ & N alkyl, YiY2NC (〇)-, YiY2NS02- and- S〇2NYiY2, in which Υι and 22 are the same or different, and are independently selected from the group consisting of 笱, 栌 I _2, ^ 砭, squaryl, cycloalkyl, and aryl. "Ring system substituent, 4 L j to represent a single moiety that simultaneously replaces two hydrogens on two available hydrogens on two adjacent carbon atoms on the ring system). An example of this moiety is methyldioxy Methoxy, -C (CH3) r, and the like, which are formed as, for example, soil—

之部份。 87870 -17- tb/ 環=^基:代表含有約3至約職環原子之非芳族飽和單 多個在二广系統，以約5至約1()個環原子較佳，其中-或 夕個在每系統中的原、 或組合的氮、氧戈择、、二 卜的元素’例如，單獨 在减"。沒有任何鄰接的氧及/或硫原子出現 環：根：：較佳的雜環基包括約5至約6個環原子。在雜 名之前附加的氮雜、氧雜或硫雜分別代表至少一 y减㈣子以環原子存在。可將任何在雜環基環中 二-顺以經保護成例如娜oc)、姆^)、_N(T〇s)基及類似物 I 也可將這些保護作用視為本發明的一部份。可將雜 二基視需要以—或多個可以相同或不相同及如本文定義： %系統取代基，，取代。可將雜環基的氮或硫原子視需要氧 =成對，之N-氧化物、s_氧化物或砂二氧化物。適合的單 裒系T隹袤基環的非限制性實例包括六氫吡啶基、吡咯烷基 A、、^氮5比嗪基、嗎琳基、硫代嗎4基”塞錢基、1，4-二氧 隹f己:k基四氫呋喃基、四氫嘍吩基、内醯胺、内醋 類似物。 應注意的是在本發明的含雜原子之環系統中，在與N、〇 或S鄰接之竣原子上沒有任何經基，以及在與另―個雜原子 鄰接的碳原子上沒有任何N或s基。因此，例如，在環中：Part of it. 87870 -17- tb / ring = ^ group: represents a non-aromatic saturated single or multiple ring system containing about 3 to about 14 ring atoms, preferably about 5 to about 1 () ring atoms, of which-or In each system, the original, or combined elements of nitrogen, oxygen, and dioxin are 'reduced individually', for example. No adjacent oxygen and / or sulfur atoms are present. Ring: Root :: Preferred heterocyclyls include about 5 to about 6 ring atoms. The aza, oxa or thia added before the miscellaneous name respectively represents that at least one y minus exists as a ring atom. Any di-cis in the heterocyclyl ring can be protected into, for example, na-oc), m ^), -N (T0s) and the like I. These protections can also be considered as part of the present invention . Heterodiyl groups can be optionally substituted with—or more—which may be the same or different and as defined herein:% system substituents. The nitrogen or sulfur atom of the heterocyclyl can be oxygen-paired, N-oxide, s-oxide or sand dioxide as required. Non-limiting examples of suitable monofluorenyl T-fluorenyl rings include hexahydropyridyl, pyrrolidinyl A, azido-5biazinyl, morphinyl, thiomorpho-4, "sekenyl, 1, 4-dioxofluorene: k-based tetrahydrofuranyl, tetrahydrofluorenyl, lactam, lactone analogs. It should be noted that in the heteroatom-containing ring system of the present invention, the There is no meridian on the contiguous atom of S and no N or s group on the carbon atom adjacent to another heteroatom. Therefore, for example, in a ring:

沒有任何-0H直接附接於以2及5標記之碳上。 也應注意的是如，例如·· 87870 -18- 200412967No -0H is directly attached to the carbons marked 2 and 5. It should also be noted that, for example, 87870 -18- 200412967

之4伤的互.¼:體形式在本發明特定的具體實施例中被視為 是相同的。 以“炔烷基”代表其中炔基及烷基係如先前所述之炔基-烷 基。較佳的炔烷基包括低碳炔基及低碳烷基。與母體部份 係經由坑基結合。適合的玦燒基的非限制性實例包括块丙 基甲基。 以“雜芳烷基”代表其中雜芳基及烷基係如先前所述之雜 芳基-燒基。較佳的雜芳烷基包括低碳烷基。適合的雜芳烷 基的非限制性實例包括吡啶基甲基及喹啉基甲基。與母 體部份係經由烷基結合。 以“經燒基”代表其中烷基係如先前定義之H〇-烷基。較佳 的經燒基包括低碳烷基。適合的羥烷基的非限制性實例包 括羥甲基及2-羥乙基。 以“酸基’’代表其中各種基係如先前所述之H-C(0>、烷基· C(O)-或環燒基-C(0>。與母體部份係經由羰基結合。較佳的 酉盈基包括低碳燒基。適合的醯基的非限制性實例包括甲醯 基、乙醯基及丙醯基。 以“芳驢基”代表其中芳基係如先前所述之芳基-c(〇>。與 母體邵份係經由羰基結合。適合的芳醯基的非限制性實例 包括苯醯基及1-萘醯基。 以“烷氧基”代表其中烷基係如先前所述之烷基-〇_。適合 的烷氧基的非限制性實例包括甲氧基、乙氧基、正丙氧基 87870 -19- 200412967 、異丙氧基及正丁氧基。與母體部份係經由醚氧結合。 以“芳氧基”代表其中芳基係如先前所述之芳基-〇-。適合 的芳氧基的非限制性實例包括苯氧基及萘氧基。與母體部 份係經由醚氧結合。 以“芳烷氧基”代表其中芳烷基係如先前所述之芳烷基-〇-。適合的芳烷氧基的非限制性實例包括芊氧基及1-或2-莕甲 氧基。與母體部份係經由醚氧結合。 以“烷硫基”代表其中烷基係如先前所述之烷基。適合 的烷硫基的非限制性實例包括甲硫基及乙硫基。與母體部 份係經由硫結合。 以“芳硫基”代表其中芳基係如先前所述之芳基-S-。適合 的芳硫基的非限制性實例包括苯硫基及莕硫基。與母體部 份係經由硫結合。 以“芳烷硫基”代表其中芳烷基係如先前所述之芳烷基-S-。適合的芳烷硫基的非限制性實例包括苄硫基。與母體部 份係經由硫結合。 以“烷氧基羰基”代表烷基-〇-ca。適合的烷氧基羰基的 非限制性實例包括甲氧基羰基及乙氧基羰基。與母體部份 係經由後基結合。 以“芳氧基羰基”代表芳基-〇-c(〇>·。適合的芳氧基羰基的 非限制性實例包括苯氧基羰基及莕氧基羰基。與母體部份 係經由羰基結合。 以“芳烷氧基羰基”代表芳烷基-〇-c(〇)-。適合的芳烷氧基 羰基的非限制性實例包括苄氧基羰基。與母體部份係經由 87870 -20- 200412967 羰基結合。 以“烷磺醯基”代表烷基-s(〇2)-。以那些其中烷基係低碳烷 基 < 基較佳。與母體部份係經由磺醯基結合。 以芳、I基代表芳基-S(〇2)_。與母體部份係經由福醯基 結合。 〃 以經取代術語代表以選自指定的基置換在選定的原子 上的一或多個氫原子，其先決條件係不超過選定的原子在 現存環境下的正常價數及以取代作用生成安定的化合物。 取代基及/或變異體之結合物受到許可，假設這些結合物會 生成安定的化合物。以“安定的化合物，，或“安定的結構，，代 表自反應混合物充份健全分離成有用的純度及調配成有效 率的治療劑之化合物。 以視需要經取代”術語代表以指定的基、基團或部份視 需要取代。 以“分離，，或化合物的“分離形式，，表示在自合成法分離之 後或來自天然來源的該化合物或其結合物的物理狀態。以 “純化”或化合物的“純化形式，，表示自純化法或本文所述之 方法或熟悉的技術員熟知的方法獲得之後的該化合物的物 理狀態，具有以本文所述或熟悉的技術員熟知的標準分析 技術為特徵之充份純度。 也應注意的是假設在本文的文章、方程式、實例及表格 中任何具有不滿意的價數之雜原子具有使價數滿意的氫原 子。 在將化合物中的官能基稱為“經保護”時，則其代表當化 87870 200412967 合物進行反應時具有修改型的基，預先阻止在保護位置上 不希望的副反應。那些一般熟悉本技藝的人與以參考標準 的參考書（如例如T. W·桂尼（Greene)等人之Protective Groups in organic Synthesis (1991)，Wiley，New York)認知適合的保護基。 當任何變異體（例如，芳基、雜環、R2等）在任何成份或 式III中出現一次以上時，則其在每一種情況中的定義與其 在每一種其它情況中的定義無關。 如本文所使用的“組合物”術語希望包含含有指定量的指 定成份之產物與任何自指定量的指定成份之結合物直接或 間接生成的產物。 本文也涵蓋本發明化合物的前體藥物及媒合物。如本文 所使用的“前體藥物”術語代表係藥物前驅體之化合物，在 一經投予病人時，以代謝或化學過程進行化學轉化作用， 產生式III化合物或其鹽及/或媒合物。在A.C.S. Symposkim Series之 Τ·亥固奇（Higuchi)及 V·史黛拉（Stella)之 Pro-drugs as Novel Delivery Systems (1987) ϋ及在 Bioreversible Carriers in Drug Design， (1987)愛德華（Edward) B.羅曲（Roche)編輯之 American Pharmaceutical Association and Pergamon Press中提供前體藥物的討論，將兩種 併入本文以供參考。 以“媒合物”代表本發明化合物與一或多種溶劑分子的物 理缔結作用。該物理缔結作用包含不同的離子及共溶劑鍵 結程度，包括氫鍵結。在特定的實例中，媒合物能夠分離 ，例如，在將一或多個溶劑分子併入結晶固體的晶格中時 。“媒合物”包含溶液相及可分離媒合物兩種。適合的媒合 87870 -22- 200412967 物的非限制性實例包括乙醇酸鹽、 合物，，係纟中溶劑分子健2〇之媒合物喊鹽及類似物。“水 “有效量”或“有效治療劑量 ° 。 此產生預期的治療、改呈、扣：未說明有效抑·及因 物量或組合物量。 卩4預防效果的本發明化合 式III化合物可以形成也在本發， 明的式III化合物當钬包括並a 、鹽類。本又說 田…、包括其鹽類的說明，除非有直它另外 的指定。如本文所使用的“鹽 說 /、 機酸所形成的酸性鹽㈣以&機及/或有 ^, …、以播機及/或有機鹼所形成的鹼性 鹽類。此外，當式m化合物包括驗性部份（如心或味嗤， 但不限於此）及酸性部份（如錢，但不限於此）時，則可以 形成及包括在本文所使用的“鹽（類），，術語内的兩性離子内 鹽類”）。以在醫藥上可接受之鹽類（在身體上可接受的無毒 性鹽類）較佳，雖然其它的鹽類也有用。例如，以式m化合 物分別與酸量或鹼量（如等量）在介質中（如使鹽沉澱之介質） 或在水性介質中反應，接著以親液化作用，可以形成式m 化合物的鹽類。 以貝例說明的酸加成鹽類包括醋酸鹽、抗壞血酸鹽、苯 甲酸鹽、苯續酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸 鹽、樟腦酸鹽、樟腦磺酸鹽、富馬酸鹽、氫氯酸鹽、氫溴 酸鹽、氫碘酸鹽、乳酸鹽、馬來酸鹽、甲烷磺酸鹽、萘橫 酸鹽、確酸鹽、草酸鹽、$粦酸鹽、丙酸鹽、水楊酸鹽、號 珀酸鹽、硫酸鹽、酒石酸鹽、硫代氰酸鹽、甲苯磺酸鹽（也 係已知的甲苯磺酸鹽）及類似物。此外，例如以s.博格 87870 -23 - 200412967 (Berge)等人之 Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. 高德（Gould)之 International J. of Pharmaceutics (1986) 33 201-217 ;紐 約Academic出版社的安德森（Anderson)等人之The Practice of Medicinal Chemistry (1996)及在丁he Orange Book (華盛頓 D.C.的食 品藥物管理局（Food & Drug Administration)的網頁上）討論通常 被視為適合於自鹼性醫藥化合物形成在醫藥上有用的鹽類 之酸。將這些揭示内容併入本文以供參考。 以實例說明的鹼性鹽類包括銨鹽、鹼金屬鹽類（如鈉、鋰 及鉀鹽）、鹼土金屬鹽類（如鈣及鎂鹽）、具有有機鹼之鹽類 (例如，有機胺，如二環己胺、三級-丁胺）及具有胺基酸之 鹽類（例如，精胺酸、賴胺酸及類似物）。可將鹼性含氮基 以如低碳烷基鹵（甲基、乙基及丁基氯、溴及碘）、硫酸二 烷基酯（例如，硫酸二甲酯、二乙酯及二丁酯）、長鏈鹵化 物（例如，癸基、月桂基及硬脂基氯、溴及碘）' 芳烷基鹵 (例如，苄基及苯乙基溴）及其它之類的試劑季鹼化。 希望所有這些酸性鹽類及驗性鹽類係在本發明範圍内的 在醫藥上可接受之鹽類，並將所有酸性及鹼性鹽類視為以 本發明為目的的對應化合物之自由形式的等同物。 式III化合物及其鹽類、媒合物和前體藥物可以其互變體 形式存在（例如，成為醯胺或亞胺醚）。在本文涵蓋所有的 這些互變體形式，成為本發明的一部份。 在本發明的範圍内涵蓋本發明化合物（包括化合物的那些 鹽類、媒合物和前體藥物與前體藥物的鹽類和媒合物）所有 的立體異構物（例如，幾何異構物、光學異構物及類似物） 87870 -24- 200412967 ，如那些由於在各種取代基上不對稱的碳而可以存在的立 體異構物，包括對映異構形式（其甚至在沒有不對稱的碳存 在下而可以存在）、幾何異構形式、滯轉異構形式及非對映 異構形式，成為位置異構物（如例如4-吡啶基及3-吡啶）。本 發明化合物的各個立體異構物可以例如幾乎不含其它異構 物，或可以摻合，成為外消旋物，或與所有其它或其它經 選擇之立體異構物摻合。本發明的對掌性中心可以具有如 以IUPAC 1974推荐書所定義之S或R組態。希望的“鹽”、“媒 合物”、“前體藥物”及類似術語的使用同樣適用於本發明化 合物的對映異構物、立體異構物、幾何異構物、互變體、 位置異構物、外消旋物或前體藥物的鹽、媒合物和前體藥 物。 根據本發明的化合物具有醫藥特性：特定言之，式III化 合物可以係蛋白激酶抑制劑，如例如週期素依賴性激酶抑 制劑、以促細胞***劑活化之蛋白激酶（MAPK/ERK)、糖原 合成酶激酶3 (GSK3p)及類似物。週期素依賴性激酶（CDK)包 括例如 CDC2 (CDK1)、CDK2、CDK4、CDK5、CDK6、CDK7 和 CDK8。期待新穎的式III化合物係增殖性疾病治療法中有用 的化合物，如癌症、自身免疫疾病、病毒疾病、霉菌性疾 病、神經性/神經變性異常、關節炎、發炎、抗增殖性（例 如，眼部視網膜病變）、神經元、脫髮及心血管疾病。在以 上引用的U.S. 6,413,974中陳列許多這些疾病及異常，將該揭 示内容併入本文以供參考。 更特定言之，式III化合物可用於治療各種癌症，包括（但 87870 -25 - 200412967 不限於此）以下：瘤，包括膀胱瘤、***瘤、直腸瘤、腎瘤 、肝瘤、肺瘤（包括非小細胞肺癌）、食道瘤、膽囊瘤、卵 巢瘤、胰臟瘤、胃瘤、子宮頸瘤、甲狀腺瘤、攝護腺瘤及 皮膚瘤（包括鱗狀細胞瘤）； 淋巴系統的造血腫瘤，包括白血病、急性淋巴細胞性白 血病' 急性淋巴性白血病、B-細胞淋巴瘤、T-細胞淋巴瘤 、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、髮狀細胞淋巴瘤 及巴奇氏（Burkett’s)惡性淋巴瘤； 骨髓細胞系統的造血腫瘤，包括急性和慢性骨髓性白血 病、骨髓發育不良徵候群及前骨髓細胞白血病； 間葉來源的腫瘤，包括纖維肉瘤及橫紋肌肉瘤； 中樞及末梢神經細統的腫瘤，包括星狀細胞瘤、神經細 胞瘤、神經膠質瘤及神經鞘瘤；及 其它腫瘤，包括黑色素細胞瘤、***細胞瘤、畸胎癌、 骨癌、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌及卡波 西氏（Kaposi’s)肉瘤。 由於CDK在一般細胞增殖的調節作用中的關鍵性角色， 可將抑制劑當作可逆式細胞抑制劑，其可用於治療任何以 不正㈣細胞增殖為特點的疾病過程，例如，良性攝護腺 肥大、冢族性大腸腺腫症、神經纖維瘤、動脈粥樣硬化症 、肺纖維化、關節炎、牛皮癬、腎絲球腎炎、在血管形成 術或血管手術之後的再狹窄症、肥厚性症痕形&、發炎性 腸道疾病、移植排斥、内毒性休克及霉菌性咸染。 式職合物也可用於治療阿兹海默氏病二最近的發現 87870 -26- 200412967 建議CDK5涉及變性蛋白質的磷酸化作用（J. Biochem，（1995) Π7, 74 卜749) 〇 式III化合物可以謗發或抑制細胞凋零。細胞凋零反應係 各種人類疾病中的異常。作為細胞凋零調節劑的式ΠΙ化合 物可用於治療癌症（包括那些上述型式的癌症，但不限於 此）、病毒感染（包括苑療病毒、痘病毒、愛波斯坦-巴爾 (Epstein-Barr)病毒、辛德比斯（Sindbis)病毒及腺病毒，但不限 於此）、預防在以HIV感染之個體中發生AIDS、自身免疫疾 病（包括全身性紅斑性狼瘡、紅斑性狼瘡、以自身免疫介入 之腎絲球腎炎、類風濕性關節炎、牛皮癖、發炎性腸道疾 病及自身免疫性糖尿病，但不限於此）、神經變性異常（阿 兹海默氏病、以AIDS介入之癡呆症、巴金生氏病、肌萎縮 性脊髓側索硬化症、視網膜色素變性、脊髓性肌肉萎縮症 及小腦退化症，但不限於此）、骨髓發育不良徵候群、再生 不良性貧血、與心肌梗塞有關連的缺血性傷害、中風和再 灌注傷害、心律不整、動脈粥樣硬化症、以毒素誘發或與 酒精有關的肝疾病、造血功能性疾病（包括慢性貧血及再生 不良性貧血，但不限於此）、肌肉骨骼系統的退化性疾病 (包括骨質疏鬆症及關節炎，但不限於此）、阿司匹靈敏感 性鼻竇炎、囊腫纖維化、多發性硬化症、腎臟疾病及癌症 疼痛。 作為CDK抑制劑的式in化合物可以調節細胞rnA及DNA合 成程度。這些試劑因此可用於治療病毒感染（包括HIV、人 類乳哭狀病毒、疱疹病毒、痘病毒、愛波斯坦-巴爾病毒、 87870 -27- 200412967 辛德比斯病毒及腺病毒，但不限於此）。 式III化合物也可用於癌症的化學預防作用。將化學預防 作用定義成以或阻斷使突變事件開始或阻斷已承受傷堂之 癌症前期的細胞進展或抑制腫瘤復發的方式抑制侵犯Z癌 症的發生。 式III化合物也可用於抑制腫瘤血管新生及轉移。 式III化合物也可以當作其它的蛋白激酶抑制劑（例如，蛋 白激酶 C、her2、ran、MEK1、MAP 激酶、EGF受體、PDGF 受髀 、IGF X體、PI3激酶、weel激酶、Src、八⑷及因此有效治療 與其i蛋白激酶有關連的疾病。 本發明的另一個觀點係治療具有與CDK有關連的疾病或 症狀（哺乳類（例如，人類）的方法，其係以有效治療劑量 的至少一種式III化合物或該化合物在醫藥上可接受之鹽气 媒合物投予哺乳類。 較佳的劑量係約0·001至5〇〇毫克/以公斤計之體重/天之式 III化合物。尤其較佳的劑量係約〇 〇1至25毫克/以公斤計之 體重/天之式III化合物或該化合物在醫藥上可接受之鹽或媒 合物。 本發明的化合物也可用於與一或多種抗癌症治療（如照射 治療法）及/或與一或多種抗癌劑的組合療法（一起或連續投 藥），如選自由細胞抑制劑、胞毒劑（如例如DNA交互作用 劑（如順氣氨鉑（cisplatin)或阿霉素（d〇x〇rubicin)，但不限於此） 、糸杉Ί (例如’ Μ癌易（tax〇tere)、紅豆杉醇（咖⑷）' 拓樸 異構酶11抑制劑（如順銷）、拓樸異構酶I抑制劑（如伊利替康 87870 -28- 200412967 (irinotecan)(或CPT-ll)、刊普托斯塔（camptostar)或托波替康 (topotecan))、微管交互作用劑（如紫杉醇、歐洲紫杉醇（docetaxel) 或埃波霉素（epothilones))、荷爾蒙劑（如三苯氧胺）、胸嘗酸合 成酶抑制劑（如5-氟尿嘧啶）、抗代謝劑（如氨甲蝶呤）、烷基 化試劑（如帝蒙柔羅麥德（temozolomide)(來自新澤西州肯尼沃 斯（Kenilworth)之仙靈葆雅（Schering-Plough)公司的 TEMODAR™) 、壤鱗驗胺）、法呢基蛋白轉移酶抑制劑（如來自新澤西州 肯尼沃斯之仙靈葆雅公司的SARASAR™ (4-[2-[4-[(llR)-3，10-二溴基-8-氣基-6，11-二氫-5H-苯并[5,6]環庚[l，2-b]吡啶-11-基]-1_六氫吡啶基]-2-氧乙基]-1-六氫吡啶羧醯胺或SCH 66336)、提皮法尼畢(tipifamib)(來自楊森製藥(Janssen Pharmaceuticals) 之 Zamestra(S^ R115777)、L778,123 (來自新澤西州白屋站（Whitehouse Station)之默克公司（Merck & Company)的法呢基蛋白轉移酶抑 制劑）、BMS 214662(來自新澤西州普林斯頓（Princeton)之必治 妥施貴寶製藥（Bristol-Myers Squibb Pharmaceuticals)的法呢基蛋白 轉移酶抑制劑））、信號轉導抑制劑（如艾瑞沙（Iressa)(來自英 國阿斯特捷利康（Astra Zeneca)製藥）、塔西伐（Tarceva)(EGFR激 酶抑制劑）、EGFR的抗體（例如，C225)、GLEEVEC®(來自新 澤西州東漢語威市（East Hanover)之諾華（Novartis)製藥的C-abl 激酶抑制劑））、干擾素（如例如内含子（來自仙靈葆雅公司） 、長效干擾素（來自仙靈葆雅公司））、荷爾蒙治療組合法、 芳香酶組合法、ara-C、亞德里亞霉素、環磷醯胺及吉西它 賓（gemcitabine)所組成的群組之抗癌劑。 其它的抗癌劑（也稱為抗腫瘤劑）包括（但不限於此）尿哺p定 87870 -29- 200412967 氮芬、氮芬、異環磷醯胺（Ifosfamide)、美法蘭（Melphalan)、 苯丁酸氮芥、皮波伯曼（Pipobroman)、三乙撐蜜胺、三乙撐 硫代磷酸醯胺、白消安（Busulfan)、卡幕司他汀（Carmustine)、 路幕司他汀（Lomustine)、鏈脲佐菌素、達卡巴畔（Dacarbazine) 、氟脫氧尿菩、阿糖胞甞、6-鏡基嗜呤、6-硫代鳥嗓呤、氟 達拉賓（Fludarabine)磷酸鹽、奥沙利鉑（oxaliplatin)、硫可維瑞 (leucovirin)、奥沙利賓（來自法國赛語菲聖德拉堡製藥（Sanofi-Synthelabo Pharmaceuticals)之ELOXATIN™)、潘托司他汀（pentostatine) 、長春花鹼、長春新鹼、長春地辛、博萊霉素、放線霉素 、道諾紅菌素、阿霉素、表阿霉素（Epirubicin)、伊達比辛 (Idarubicin)、光神霉素、脫氧肋間型霉素（Deoxycoformycin)、絲 裂霉素-C、L-天冬酸胺酶、替尼泊答（Teniposide) 17α-块雌二 醇、二乙基己烯雌酚、睪酮、脫氫可的松、氟甲睪酮 (Fluoxymesterone)、拓莫斯丹諾酮（Dromostanolone)丙酸鹽、睪 内酯（Testolactone)、甲地孕酮醋酸鹽、甲基脫氫皮醇、甲基 睪酮、脫氫皮醇、氫經脫氫皮醇、氯晞雌醚（Chlorotrianisene) 、經基孕激素類、胺格魯米德（Aminoglutethimide)、雌莫司汀 (Estramustine)、甲孕酮（Medroxyprogesterone)酷酸鹽、琉普利德 (Leuprolide)、氟塔麥德（Flutamide)、托瑞米芬（Toremifene)、固 色林（Goserelin)、順氯氨鉑、卡鉑（Carboplatin)、經基脲、安吖 淀（Amsacrine)、普卡巴胖（Procarbazine)、米托坦（Mitotane)、米 托杉酮（Mitoxantrone)、左美素（Levamisole)、納維賓（Navelbene) 、安納退吐（Anastrazole)、來退吐（Letrazole)、孰普西塔賓 (Capecitabine)、瑞羅杉芬（Reloxafme)、拓羅山芬（Droloxafine)或 87870 -30- 200412967 7T甲基金胺。 如果調配成固定劑量時，則這些結合產物使用在本文所 述之劑量範圍内的本發明化合物及其它在其劑量範圍内的 醫樂活性劑或治療劑。例如，已發現CDC2抑制劑歐魯幕辛 (ΟΙ。—)與祕胞调零的已知的胞毒劑具有細用(jThe four-dimensional form is considered to be the same in a particular embodiment of the invention. "Alkynyl" represents an alkynyl-alkyl group in which the alkynyl and alkyl groups are as previously described. Preferred alkynyl groups include lower alkynyl and lower alkyl. It is combined with the parent body via pit foundation. Non-limiting examples of suitable fluorenyl groups include block propylmethyl. "Heteroaralkyl" represents a heteroaryl-alkyl group in which heteroaryl and alkyl are as previously described. Preferred heteroaralkyls include lower alkyl. Non-limiting examples of suitable heteroarylalkyl groups include pyridylmethyl and quinolinylmethyl. It is bonded to the parent moiety via an alkyl group. "Carbonyl" represents a H0-alkyl group in which the alkyl group is as previously defined. Preferred calcined groups include lower alkyl groups. Non-limiting examples of suitable hydroxyalkyl include hydroxymethyl and 2-hydroxyethyl. "Acid group" represents various groups in which HC (0 >, alkyl · C (O)-or cycloalkenyl-C (0 >) is as described above. It is bonded to the parent moiety via a carbonyl group. The fluorenyl group includes a low-carbon alkynyl group. Non-limiting examples of suitable fluorenyl groups include formamyl, acetamyl, and propionyl. "Aryl" represents an aryl group in which the aryl group is as previously described -c (〇 >. Combined with the parent group via a carbonyl group. Non-limiting examples of suitable arylfluorenyl groups include phenylfluorenyl and 1-naphthylfluorene. Represented by "alkoxy" where the alkyl group is as previously Non-limiting examples of the alkyl-〇. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy 87870-19-200412967, isopropoxy and n-butoxy. Some are bonded via ether oxygen. "Aryloxy" represents aryl-0- where aryl is as previously described. Non-limiting examples of suitable aryloxy include phenoxy and naphthyloxy. And The parent moiety is bonded via ether oxygen. "Aralkoxy" represents an aralkyl-0- wherein the aralkyl is as previously described. Non-limiting suitable aralkyloxy Illustrative examples include fluorenyloxy and 1- or 2-fluorenylmethoxy. They are bonded to the parent moiety via ether oxygen. "Alkylthio" represents an alkyl group in which the alkyl group is as previously described. Suitable alkylthios Non-limiting examples of methyl groups include methylthio and ethylthio. The parent moiety is bonded via sulfur. "Arylthio" represents an aryl-S- group in which the aryl is as previously described. Suitable arylthio Non-limiting examples of phenyl groups include phenylthio and sulfanyl. The parent moiety is bonded via sulfur. "Aralkylthio" represents an aralkyl-S- wherein the aralkyl is as previously described. Suitable Non-limiting examples of aralkylthio include benzylthio. The parent moiety is bonded via sulfur. "Alkoxycarbonyl" represents alkyl-0-ca. Non-limiting examples of suitable alkoxycarbonyl Including methoxycarbonyl and ethoxycarbonyl. It is bonded to the parent moiety via a post group. "Aryloxycarbonyl" represents aryl-0-c (〇 > .. Non-limiting suitable aryloxycarbonyl Illustrative examples include phenoxycarbonyl and fluorenyloxycarbonyl. The parent moiety is bonded via a carbonyl group. "Represents aralkyl-0-c (〇)-. Non-limiting examples of suitable aralkyloxycarbonyl groups include benzyloxycarbonyl. The parent moiety is bound via 87870-20-200412967 carbonyl group. "Amidino" represents alkyl-s (〇2)-. Among those, alkyl-based lower alkyl < groups are preferred. They are bonded to the parent moiety via a sulfonyl group. Aryl and I groups represent aryl- S (〇2) _. Associated with the parent moiety via fluorenyl. 〃 Represented by substituted terms to replace one or more hydrogen atoms on a selected atom with a group selected from a specified group, the prerequisite is no more than The normal valence of the selected atom in the existing environment and the substitution effect generate stable compounds. Combinations of substituents and / or variants are permitted, assuming that these combinations will generate stable compounds. A "stable compound," or "stable structure," represents a compound that is adequately and soundly separated from the reaction mixture into a compound of useful purity and formulated as an effective therapeutic agent. The term "substituted as necessary" means that the specified group, group or part is substituted as needed. "Isolated," or "isolated form of a compound," means that the compound or The physical state of the conjugate. In "purified" or "purified form" of the compound, it means the physical state of the compound after it has been obtained by purification or by the methods described herein or methods familiar to a skilled technician, having Or standard analytical techniques well known to skilled technicians are characterized by sufficient purity. It should also be noted that any heteroatom with an unsatisfactory valence in the articles, equations, examples, and tables of this article is assumed to have a satisfactory hydrogen atom. When a functional group in a compound is referred to as "protected", it represents a modified group when the compound is reacted to prevent an unwanted side reaction at a protected position in advance. Those generally familiar with the art and reference books such as, for example, Protective Groups in Organic Synthesis (1991), Wiley, New York by T. W. Greene et al., Recognize suitable protecting groups. When any variant (eg, aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula III, its definition in each case is independent of its definition in every other case. The term "composition" as used herein is intended to encompass a product containing a specified amount of a specified ingredient and any product directly or indirectly generated from a combination of the specified amount of a specified ingredient. Prodrugs and vehicles of the compounds of the invention are also encompassed herein. The term "prodrug" as used herein refers to a compound that is a precursor of a drug that, once administered to a patient, undergoes chemical transformation through metabolic or chemical processes to produce a compound of formula III or a salt and / or vehicle thereof. Hi-chi in ACS Symposkim Series and Pro-drugs as Novel Delivery Systems (1987) in V. Stella and Bioreversible Carriers in Drug Design, (1987) Edward B A discussion of prodrugs is provided in the American Pharmaceutical Association and Pergamon Press, edited by Roche, both of which are incorporated herein by reference. The "intermediate" represents the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves different degrees of ionic and co-solvent bonding, including hydrogen bonding. In particular examples, the vehicle can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Vehicle" includes both a solution phase and a separable vehicle. Non-limiting examples of suitable mate 87870 -22-200412967 include glycolate, hydrate, solvate, and the like in the solvent molecule ketone 20 in the system. "Water" effective amount "or" effective therapeutic dose ° ". This results in the expected treatment, presentation, and deduction: no indication of effectiveness or the amount of the substance or composition. (4) The compound of the present invention having a preventive effect. The compound of formula III can also be formed in the present invention. The compound of formula III as shown in the present invention includes hydrazone and salts. Ben also said that ..., including the description of its salts, unless otherwise specified. As used herein, "acid salts formed by salts, organic acids, & organic and / or ^, ..., basic salts formed by drills and / or organic bases. In addition, when the formula When the m compound includes an experimental moiety (such as heart or miso, but is not limited to this) and an acidic moiety (such as money, but is not limited to this), it can form and include "salts" as used herein, , Zwitterionic salts within the term "). Medically acceptable salts (non-toxic salts that are physically acceptable) are preferred, although other salts are also useful. For example, compounds of formula m Reacting with the acid amount or alkali amount (such as the same amount) in a medium (such as a medium for precipitating salt) or in an aqueous medium, followed by lyophilization, can form salts of the compound of the formula m. Acid addition salts include acetate, ascorbate, benzoate, benzoate, bisulfate, borate, butyrate, citrate, camphor, camphor sulfonate, and fumarate , Hydrochloride, hydrobromide, hydroiodate, lactate, maleate, formazan Sulfonates, Naphthalenes, Acetic Acids, Oxalates, Acetic Acids, Propionates, Salicylates, Percolates, Sulfates, Tartrates, Thiocyanates, Toluene (Also known as tosylate) and the like. In addition, for example, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19 from s. Berg 87870 -23-200412967 (Berge) et al. ; P. Gould's International J. of Pharmaceutics (1986) 33 201-217; The Practice of Medicinal Chemistry (1996) by Anderson et al. Of Academy Press, New York; and Ding He Orange Book (Washington, DC) DC's Food & Drug Administration web page) discusses acids that are generally considered to be suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds. These disclosures are incorporated herein by reference Examples of basic salts include ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), and salts with organic bases (for example, organic amines). , Such as dicyclohexylamine, tertiary-butylamine) and have Salts of basic acids (eg, arginine, lysine, and the like). Basic nitrogen-containing groups such as lower alkyl halides (methyl, ethyl and butyl chloride, bromine and iodine), Dialkyl sulfates (for example, dimethyl sulfate, diethyl and dibutyl esters), long chain halides (for example, decyl, lauryl and stearyl chloride, bromine and iodine) 'aralkyl halides ( For example, benzyl and phenethyl bromide) and other reagents are quaternized. It is hoped that all of these acidic salts and test salts are pharmaceutically acceptable salts within the scope of the present invention, and all acidic and basic salts are regarded as the free form of the corresponding compounds for the purpose of the present invention. Equivalent. Compounds of formula III and their salts, solvates and prodrugs may exist in their tautomeric form (e.g., as amidine or imine ether). All these tautomeric forms are covered herein as part of the present invention. Within the scope of the present invention, all stereoisomers (eg, geometric isomers) of the compounds of the present invention (including those salts, solvates, and prodrugs , Optical isomers, and the like) 87870 -24- 200412967, such as those stereoisomers that can exist due to asymmetric carbons on various substituents, including enantiomeric forms (which even exist in asymmetric It can exist in the presence of carbon), geometrically isomeric forms, hysteresis and diastereomeric forms, and becomes positional isomers (such as 4-pyridyl and 3-pyridine). The individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be blended as racemates or blended with all other or other selected stereoisomers. The facing center of the present invention may have an S or R configuration as defined in the IUPAC 1974 recommendation. The use of the desired "salt", "vehicle", "prodrug" and similar terms is equally applicable to the enantiomers, stereoisomers, geometric isomers, tautomers, positions of the compounds of the invention Isomers, racemates, or salts of prodrugs, vehicles, and prodrugs. The compounds according to the invention have medicinal properties: in particular, compounds of formula III may be protein kinase inhibitors, such as, for example, cyclin-dependent kinase inhibitors, mitogen-activated protein kinases (MAPK / ERK), glycogen Synthetase kinase 3 (GSK3p) and analogs. Cyclin-dependent kinases (CDK) include, for example, CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7, and CDK8. Novel compounds of formula III are expected to be useful compounds in the treatment of proliferative diseases, such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological / neurodegenerative disorders, arthritis, inflammation, antiproliferative properties (eg, eyes Retinopathy), neurons, hair loss, and cardiovascular disease. Many of these diseases and abnormalities are listed in U.S. 6,413,974 cited above, the disclosure of which is incorporated herein by reference. More specifically, compounds of formula III can be used to treat a variety of cancers, including (but 87870 -25-200412967 are not limited thereto) the following: tumors, including bladder tumors, breast tumors, rectal tumors, kidney tumors, liver tumors, lung tumors (including Non-small cell lung cancer), esophageal tumors, gallbladder tumors, ovarian tumors, pancreatic tumors, gastric tumors, cervical tumors, thyroid tumors, prostate tumors and dermatomas (including squamous cell tumors); hematopoietic tumors of the lymphatic system, Includes leukemia, acute lymphocytic leukemia ', acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma, and Bardoch's (Burkett's) Malignant lymphoma; Hematopoietic tumors of the bone marrow cell system, including acute and chronic myelogenous leukemia, myelodysplastic syndromes, and pre-myeloid cell leukemia; Mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; central and peripheral nerve cells Tumors, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including melanoma Sperm neuroblastoma, teratocarcinoma, bone cancer, disease, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer and Kaposi's West (Kaposi's) sarcoma. Due to the critical role of CDK in the regulation of general cell proliferation, inhibitors can be considered as reversible cytostatics, which can be used to treat any disease process characterized by unregulated cell proliferation, such as benign prostatic hypertrophy , Tsukazu colon colitis, neurofibromas, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar shape &, inflammatory bowel disease, transplant rejection, endotoxic shock, and salty mildew. Formula compounds can also be used to treat Alzheimer's disease. II. Recent findings 87870 -26- 200412967 suggest that CDK5 is involved in the phosphorylation of denatured proteins (J. Biochem, (1995) Π7, 74, 749). Compounds of formula III Can slander or suppress cell decay. Cell withering system is an abnormality in various human diseases. Compounds of formula II as modulators of cell decay can be used to treat cancers (including those described above, but not limited to them), viral infections (including garden therapy virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus, but not limited to it, prevention of AIDS in HIV-infected individuals, autoimmune diseases (including systemic lupus erythematosus, lupus erythematosus, and kidney wire with autoimmune intervention) Glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes, but not limited to this, neurodegeneration abnormalities (Alzheimer's disease, AIDS-associated dementia, Parkinson's Disease, amyotrophic lateral sclerosis, retinal pigment degeneration, spinal muscular atrophy and cerebellar degeneration, but not limited to this), myelodysplastic syndromes, aplastic anemia, ischemia associated with myocardial infarction Sexual injury, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, hematopoietic function Sexual diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive sinusitis, cystic fibers , Multiple sclerosis, kidney disease and cancer pain. Compounds of formula in which are CDK inhibitors can regulate the degree of cellular rnA and DNA synthesis. These agents are therefore useful for treating viral infections (including, but not limited to, HIV, human cough virus, herpes virus, pox virus, Epstein-Barr virus, 87870 -27- 200412967 Sindbis virus and adenovirus). Compounds of formula III are also useful for chemopreventive effects in cancer. Chemopreventive action is defined as inhibiting the occurrence of invasion of Z cancer in a manner that blocks or initiates a mutation event or blocks the progression of precancerous cells that have already suffered wounds or inhibits tumor recurrence. Compounds of formula III are also useful for inhibiting tumor angiogenesis and metastasis. Compounds of formula III can also be used as other protein kinase inhibitors (e.g., protein kinase C, her2, ran, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF X-body, PI3 kinase, weel kinase, Src, eight ⑷ and therefore effective treatment of diseases associated with its i protein kinase. Another aspect of the present invention is a method of treating a disease or symptom (mammalian (eg, human)) associated with CDK, which is at least one of an effective therapeutic dose The compound of formula III or a pharmaceutically acceptable salt aerosol of this compound is administered to mammals. The preferred dose is about 0.001 to 500 mg / kg of body weight per day of the compound of formula III. Especially compared A preferred dosage is about 0.01 to 25 mg / kg of body weight / day of a compound of formula III or a pharmaceutically acceptable salt or vehicle of the compound. The compounds of the present invention may also be used in combination with one or more antibodies. Cancer treatment (such as radiation therapy) and / or combination therapy (together or continuous administration) with one or more anticancer agents, such as selected from the group consisting of cytostatic agents, cytotoxic agents (such as, for example, DNA interaction agents (such as Cisplatin or doxorubicin, but not limited to this, cypress (for example, 'Taxoter, Taxol), Topoisomerase 11 Inhibitors (such as cis marketing), Topoisomerase I inhibitors (such as irinotecan 87870-28-200412967 (irinotecan) (or CPT-ll), Camptostar or Topotecan (topotecan)), microtubule interacting agents (such as paclitaxel, docetaxel or epothilones), hormones (such as tamoxifen), acid synthase inhibitors (such as 5-fluorouracil), Antimetabolites (such as methotrexate), alkylating agents (such as temozolomide (TEMODAR from Schering-Plough, Kenilworth, NJ) ™), lamina test), farnesyl protein transferase inhibitors (such as SARASAR ™ (4- [2- [4-[(llR) -3 , 10-dibromo-8-amino-6,11-dihydro-5H-benzo [5,6] cycloheptan [l, 2-b] pyridine-11-yl] -1_hexahydropyridyl ] -2-oxoethyl] -1-hexahydropyridine Carboxamide or SCH 66336), tipifamib (Zamestra (S ^ R115777) from Janssen Pharmaceuticals, L778,123 (Merck & Co. from Whitehouse Station, New Jersey) (Merck & Company's farnesyl protein transferase inhibitor), BMS 214662 (Fristolyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey) ), Signal transduction inhibitors (such as Iressa (from Astra Zeneca Pharmaceuticals, UK), Tarceva (EGFR kinase inhibitor), antibodies to EGFR (eg, C225 ), GLEEVEC® (C-abl Kinase Inhibitor from Novartis Pharmaceuticals of East Hanover, New Jersey), Interferons (such as introns (from Celestial Corporation), Chang Group consisting of interferon (from Celestial Corporation), hormonal therapy combination, aromatase combination method, ara-C, adriamycin, cyclophosphamide, and gemcitabine Resistance Agents. Other anticancer agents (also known as antitumor agents) include (but are not limited to) urinary papidine 87870 -29- 200412967 Azafen, Azafen, Ifosfamide, Melphalan , Phenylbutyrate, Pipobroman, Triethylenemelamine, Triethylphosphorylamide, Busulfan, Carmustine, Lumusstatin ( (Lomustine), streptozotocin, Dacarbazine, fludeoxyuridine, cytarabine, 6-mirrothin, 6-thioguanthine, fludarabine phosphate Oxaliplatin, leucovirin, oxaliplatin (ELOXATIN ™ from Sanofi-Synthelabo Pharmaceuticals, France), pentostatine , Vincristine, Vincristine, Vincristine, Bleomycin, Actinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Phytomycetin , Deoxycoformycin, Mitomycin-C, L-asparaginase, Tenipol eniposide) 17α-block estradiol, diethyldiethylstilbestrol, fluorenone, dehydrocortisone, fluoxymesterone, Dromostanolone propionate, testolactone, formazan Medroxyprogesterone acetate, methyldehydrocortisol, methylacetophenone, dehydrocortisol, hydrogen dehydrocortisol, chloroestradiol ), Estramustine, Medroxyprogesterone, Leuprolide, Flutamide, Toremifene, Goserelin , Cisplatin, Carboplatin, Carboplatin, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole ), Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafme, Droloxafine or 87870 -30- 200412967 7T methyl auramine. If formulated in a fixed dose, these combination products use the compounds of the present invention and other medicinal active or therapeutic agents within the dosage range described herein. For example, the CDC2 inhibitor Ouluxin (0. 1) has been found to have a fine use with known cytotoxic agents that zero the secretory cells (j.

Cell Sci”（1995)迦,2897)。f結合調配物不適合時，則也可將 式III化合物與已知的抗癌劑或胞毒劑連續投藥。本發明不 限於以連續投藥，可在或投予已知㈣癌劑或胞毒劑之前 ，或之後投予式m化合&，，與抗纏投藥順序會 影響週期素依賴性激酶抑制劑(氟維皮瑞多)的胞毒活性 ⑹顧:Research，（簡也3375)。這些技術係在熟悉本技藝的 人與主診醫師的技巧内。 因此，在本發明的觀點中，本發明包括含有至少一種式 ΠΙ化合物或其在醫藥上可接受之鹽或媒合物之劑量及—或 夕種以上陳列的抗癌治療和抗癌劑之劑量的結合物，其中 以化合物/治療劑之劑量得到預期的療效。 可以許多藥理檢定確認本發明化合物的藥理特性。以根 據本發明的化合物及其鹽類進行以下所述以實例說明的藥 理檢定。 本發明也關於含有至少-種式職合物或該化合物在醫 藥上可接受之鹽或媒合物及至少一種在醫藥上可接受之載 體的醫藥組合物。 為了以本發明所述之化合物製備醫藥組合物，故在醫藥 上可接受之惰性載體可以係或固體或液體。固體型製劑包 87870 31 200412967 括藥粉、藥.片、分散型藥粒、膠囊、酏劑及栓劑。藥粉及 藥片可由從約5至約95%之活性成份所組成的。在本技藝已 知適合的固體載體，例如，碳酸鎂、硬脂酸鎂、滑石粉、 糖或乳糖。可以使用適合於口服投藥的固體劑型之藥片、 藥粉、_劑及膠囊。可在賓州伊斯頓（Easton)之馬克出版公 司（Mack Publishing Co.)以 A·吉納若（Gennaro)(編輯）之第 18 版 Remington’s Pharmaceutical Sciences (1990)中發現用於各種組合物 的在醫藥上可接受之載體及製造方法的實例。 液體型製劑包括溶液、懸浮液及乳液。可以用於非經腸 注射之水或丙二醇水溶液作為實例說明，或以甜味劑及遮 光劑加入口服溶液、懸浮液及乳液中。液體型製劑也可以 包括用於鼻内投藥之溶液。 適合於吸入的喷霧製劑可以包括溶液或粉末型固體，可 以其與在醫藥上可接受之載體結合，如惰性壓縮氣體，例 如，氮氣。 也包括計劃在使用之前旋即轉化成用於或口服或非經腸 投藥之液體型製劑之固體型製劑。這些液體型包括溶液、 懸浮液及乳液。 本發明的化合物也可經皮膚輸送。皮膚用組合物可以採 用乳膏、水乳液、噴霧及/或乳液型式，並可以包括在就該 目的而言為本技藝所熟知的基質或貯存型之皮膚貼片中。 也可將本發明的化合物經皮下輸送。 化合物以經由口服投藥較佳。 醫藥製劑係以單位劑型較佳。在該劑型中，將製劑再分 87870 -32- 200412967 成包括適當的活性組份量之適當尺寸的單位劑型，例如， 達成預期目的的有效劑量。 根據特殊的應用，可將在製劑的單位劑量中的活性化合 物量從約1毫克改變或調整至約100毫克，以從約1毫克至約 50毫克較佳，以從約1毫克至約25毫克更佳。 所使用的實際劑量可依據病患的需求及欲治療的病狀嚴 重性而改變。對特殊情況適當的劑量攝取的決定係在本技 蟄的技巧範圍内。為了方便起見，可將總日劑量依需要在 一天之内分批投藥。 根據主診醫師考量如年齡、病患的病況和重量與欲治療 之徵候的嚴重性之類的因素調節本發明的化合物及/或其在 醫藥上可接受之鹽類的劑量及頻率。用於口服投藥的代表 性建議日劑量可在從約丨毫克/天至約500毫克/天為範圍的2 至4次分次劑量，以丨毫克/天至2〇〇毫克/天較佳。 本發明的另一個觀點係含有有效治療劑量的至少一種式 ra化合物或該化合物在醫藥上可接受之鹽或媒合物及在醫 藥上可接受之載體、媒劑或稀釋劑之套組。 、本發明還有的另-個觀點係含有至少_種式m化合物或 孩化合物纟醫藥上可接受之鹽或媒合物之劑量及至少一種 以上陳列的抗癌治療劑及/或抗癌劑之劑量的套組，其中以 二或多種成份之劑量得到預期的療效。 由以下的製備作用及實例為例證說明在本文揭示的本發 明，不應該將其解釋成限制本發明的範圍。那些孰悉本技 蟄的人將會明白可替換的機制路徑及類似結構。 87870 -33 - 200412967Cell Sci "(1995) Gal, 2897). When the f-binding formulation is not suitable, the compound of formula III can also be administered continuously with known anticancer or cytotoxic agents. The present invention is not limited to continuous administration, and can be administered at or on Before or after the administration of known malignant cancer agents or cytotoxic agents, the formula m compound &, and the order of anti-entanglement administration will affect the cytotoxic activity of the cyclin-dependent kinase inhibitor (fluviprido): Research, (Jane also 3375). These techniques are within the skill of those skilled in the art and the attending physician. Therefore, in the context of the present invention, the present invention includes a compound that contains at least one compound of formula III or is pharmaceutically acceptable The dosage of the salt or vehicle and / or the combination of the above-listed doses of anti-cancer treatment and anti-cancer agent, wherein the expected therapeutic effect is obtained at the compound / therapeutic agent dose. The compound of the present invention can be confirmed by many pharmacological tests Pharmacological properties. The compounds according to the present invention and their salts are subjected to the pharmacological tests described below by way of example. The invention also relates to salts containing at least one compound or a pharmaceutically acceptable salt of the compound A vehicle and a pharmaceutical composition of at least one pharmaceutically acceptable carrier. In order to prepare a pharmaceutical composition with the compound described in the present invention, a pharmaceutically acceptable inert carrier may be either solid or liquid. Solid preparation Includes 87870 31 200412967 including medicinal powder, medicine. Tablets, dispersible granules, capsules, elixirs and suppositories. Medication powders and tablets may be composed of from about 5 to about 95% of active ingredients. Suitable solid carriers are known in the art For example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Solid dosage forms of tablets, powders, pills and capsules suitable for oral administration can be used. Available from Mark, Easton, PA The company (Mack Publishing Co.) finds examples of pharmaceutically acceptable carriers and manufacturing methods for various compositions in A. Gennaro (ed.) 18th edition Remington's Pharmaceutical Sciences (1990). Liquid formulations include solutions, suspensions and emulsions. Can be used for parenteral injection of water or aqueous propylene glycol as examples, or added as sweeteners and opacifiers Solutions, suspensions and emulsions. Liquid formulations can also include solutions for intranasal administration. Spray formulations suitable for inhalation can include solutions or powdered solids, which can be combined with a pharmaceutically acceptable carrier, Such as inert compressed gas, for example, nitrogen. It also includes solid-type preparations that are intended to be converted into liquid-type preparations for oral or parenteral administration immediately before use. These liquid forms include solutions, suspensions, and emulsions. The compounds can also be delivered through the skin. Compositions for skin can be in the form of creams, water emulsions, sprays and / or emulsions and can be included in a matrix or storage type skin patch that is well known in the art for this purpose . The compounds of the invention can also be delivered subcutaneously. The compound is preferably administered orally. The pharmaceutical preparation is preferably in a unit dosage form. In this dosage form, the preparation is subdivided into 87870-32-200412967 into appropriately sized unit dosage forms including the appropriate amount of active ingredient, for example, an effective dose to achieve the intended purpose. Depending on the particular application, the amount of active compound in a unit dose of the formulation can be changed or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, and from about 1 mg to about 25 mg Better. The actual dose used may vary depending on the needs of the patient and the severity of the condition being treated. The determination of the appropriate dose for a particular situation is within the skill of this technique. For convenience, the total daily dose may be administered in portions within a day as needed. The dosage and frequency of the compound of the present invention and / or its pharmaceutically acceptable salts are adjusted according to factors such as the age, the condition and weight of the patient, and the severity of the symptoms to be treated. A representative recommended daily dose for oral administration may be in two to four divided doses ranging from about 1 mg / day to about 500 mg / day, preferably from 1 mg / day to 200 mg / day. Another aspect of the present invention is a kit comprising a therapeutically effective amount of at least one compound of formula ra or a pharmaceutically acceptable salt or vehicle of the compound and a pharmaceutically acceptable carrier, vehicle, or diluent. 2. Another aspect of the present invention is to contain at least one compound of formula m or compound m, a pharmaceutically acceptable salt or vehicle dose, and at least one or more listed anticancer therapeutic agents and / or anticancer agents. A dose set in which the desired effect is obtained at a dose of two or more ingredients. The following preparations and examples illustrate the invention disclosed herein and should not be construed as limiting the scope of the invention. Those who are familiar with this technology will understand alternative mechanisms and similar structures. 87870 -33-200412967

在提出 NMR 數據時，在或 Varian VXR-200 (200 MHz，yh)， Varian Gemini-300 (300 MHz)或 XL-400 (400 MHz)上獲得 iH光譜， 並自具有數個質子（多重性）之Me4Si的高磁場方向ppm及以括 弧表示之赫茲（Hertz)計的偶合常數提出報告。在提出LC/MS 數據時，則使用 Applied Biosystems API-100 質譜儀及 Shimadzu SCL-10ALC管柱：Altech鉑C18，3微米，33毫米x7毫米ID ;梯 度流動· 0 分鐘-10% CH3CN，5 分鐘-95% CH3CN，7 分鐘- 95% CH3CN ’ 7.5分鐘-10% CH3CN，9分鐘-終止進行分析。提供駐 留時間及觀察的母體離子。 以括弧中的縮寫可以表示以下的溶劑及試劑： 薄層色層分離法：TLC 二氯甲烷：CH2C12 醋酸乙酯：AcOEt或EtOAc 甲醇：MeOH 三氟醋酸酯：TFA 三乙胺：Et3N或TEA 丁氧基羰基：N-Boc或Boc 核磁共振光譜：NMR 液態色層分離質譜法：LCMS 鬲解析質譜法：HRMS 毫升：mL 毫莫耳·· mmol 微升：μΐ 公克：g 87870 -34 - 200412967 愛克：mg 室溫或rt(室溫）：約25°C 羞備實例1When presenting NMR data, iH spectra were obtained on Varian VXR-200 (200 MHz, yh), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz), and have several protons (multiplicity) The high magnetic field direction ppm of Me4Si and the coupling constant in Hertz expressed in parentheses are reported. When presenting the LC / MS data, an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10ALC column were used: Altech Platinum C18, 3 microns, 33 mm x 7 mm ID; gradient flow · 0 minutes-10% CH3CN, 5 minutes -95% CH3CN, 7 minutes-95% CH3CN '7.5 minutes-10% CH3CN, 9 minutes-termination for analysis. Provide dwell time and observed parent ion. The following solvents and reagents can be expressed by the abbreviations in parentheses: Thin layer chromatography: TLC dichloromethane: CH2C12 ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA triethylamine: Et3N or TEA butyl Oxycarbonyl: N-Boc or Boc Nuclear magnetic resonance spectrum: NMR Liquid chromatography-mass spectrometry: LCMS 鬲 Analytical mass spectrometry: HRMS ml: mL millimoles · mmol microliter: μ · g: 87870 -34-200412967 Love Gram: mg Room temperature or rt (room temperature): about 25 ° C Preparation Example 1

CH3 ^N^/CONH +CH3 ^ N ^ / CONH +

Br· 丙 層 將在無水c聊中的b甲基咪唉_2_幾酿胺（ι當幻與漠基 酮（1.2當量）之混合物在n2下檀掉及回流&。將溶劑芙發 並在以CHA :在Me0H中的7當量贿3之石夕膠上的管柱二 分離法之後獲得純產物。 製備實例2-5 :The Br · C layer will remove the mixture of b methyl imidazolium chloride in anhydrous C 唉 2_ jiminamine (ι Dan Huan and Mo ketone (1.2 equivalents) under n2 and reflux & The pure product was obtained after a two-column separation method using 7 equivalents of 3 briquettes in CHA: Me0H. Preparation Example 2-5:

22

與製備實例1所述基本上相同的步 製備實例6 : 驟製備這些化合物Substantially the same steps as described in Preparation Example 1

將來自製備實例1的產物（1當量）與味唆（25當量）之^ 在N2及175°C下攪拌20小時。將咪唑 土在具艾中詻餾，並將歹 餘物在以CHfl2 :在Me〇H中的7各旦\π_ι、 闲里ΝΗ3又矽膠上的管柱^ 87870 -35- 200412967 層分離法純化。獲得純產物。The product from Preparation Example 1 (1 equivalent) and miso (25 equivalents) were stirred under N2 and 175 ° C for 20 hours. The imidazolium was retorted in Moxa and the residue was purified on a column with CHfl2: 7 deniers in MeOH, π3, and silica gel ^ 87870 -35- 200412967 layer separation method . Obtained pure product.

10 的步驟製備這些化合物 與製備實例6所述基本上相同 塞」t實例一 11 :The steps of 10 to prepare these compounds are essentially the same as described in Preparation Example 6) Example 1 11:

、將在POCI3 (30當量）中來自製備實例6的產物當量）與毗 哫（0.75當量）之混合物在$下攪拌及回流5小時。將混合物 倒入冰中’以10% Na0H水溶液中和及以ch^2萃取。將萃取 物經NajO4乾燥，過濾及將溶劑蒸發。在以 矽膠上的管柱色層分離法得到純產物。 M備實例12-1 s ：2. The mixture of the product equivalents from Preparation Example 6 in POCI3 (30 equivalents) and pyrene (0.75 equivalents) was stirred and refluxed at $ 5 for 5 hours. The mixture was poured into ice 'and neutralized with 10% NaOH aqueous solution and extracted with ch ^ 2. The extract was dried over NajO4, filtered and the solvent was evaporated. Pure product was obtained by column chromatography on silica gel. M standby instance 12-1 s:

87870 36- 200412967 的步驟製備這些化合物 與製備實例11所述基本上相同 實例16 :87870 36- 200412967 using the same procedure to prepare these compounds as described in Preparation Example 11 Example 16:

CI 一將來自製備實例⑽產物（1當量）、3_(胺甲基）峨淀（11當 里）、-異丙基乙胺（20當量）與無水二嚼垸之混合物在贼 及N2下稅掉48小時。將溶匈义 才/合釗瘵發，並將殘餘物在以 CH2Cl2/MeOH/濃縮水性丽〇11之 <咬胗上的管柱色層分離法純 化。獲得純產物。 實例17-20 :CI-1 will be a mixture of the product from the preparation example (1 equivalent), 3- (aminemethyl) Edo (11 equivalents), -isopropylethylamine (20 equivalents), and anhydrous diisocyanate. The tax will be levied on thieves and N2. 48 hours. The solution was dissolved in Hung Hoi Yee / He Zhaozhao, and the residue was purified by column chromatography on a CH2Cl2 / MeOH / concentrated water-based resin. Obtained pure product. Examples 17-20:

與製備實例⑹斤述基本上相 實例21 : 同的步驟製備這些化合物 87870 -37- 200412967Basically the same as in Preparation Example Example 21: These compounds were prepared in the same procedure 87870 -37- 200412967

將來自製備實例的產物（1當量）、乙醯氯（3當量）、二異丙 基乙胺（6當量）與無水12-二氯乙烷之混合物在n2下回流24小 時。將混合物倒入飽和水性NaHC〇3中，以CH2C12萃取及將萃 取物經ΝΜ〇4乾燥。將溶劑蒸發，並將殘餘物在以CH2Cl2/The product from the preparation example (1 equivalent), acetamidine (3 equivalents), a mixture of diisopropylethylamine (6 equivalents) and anhydrous 12-dichloroethane was refluxed under n2 for 24 hours. The mixture was poured into saturated aqueous NaHC03, extracted with CH2C12 and the extract was dried over NM04. The solvent was evaporated and the residue was treated with CH2Cl2 /

EtOAc之碎膠上的管柱色層分離法純化，產生純產物。 音例 22-25 ··Purification by column chromatography on EtOAc gels yielded pure product. Examples 22-25

步·驟製備這些化合物 與製備實例21所述基本上相同的 實例: 'Steps to prepare these compounds are essentially the same as described in Preparation Example 21:

87870 -38. 200412967 在無水CHsCN中的通s (1當量）之溶液在叫下加入在無水 CH3CN中來自製備實例的產物〇當量）之揽掉溶液中。將混 合物在25 °C下攪拌2小時及接著將溶劑蒸發。在以 EtOAc/MeOH之發膠上的色層分離法供給產物。 實例27-30 :87870 -38. 200412967 A solution of 1 s in hydrated CHsCN was added to the solution and added to the solution. The mixture was stirred at 25 ° C for 2 hours and then the solvent was evaporated. The product was supplied as a chromatographic separation on a hair gel with EtOAc / MeOH. Examples 27-30:

2727

與製備實例26所述基本上相同的步驟製備這些化合物。 實例31 ：These compounds were prepared in substantially the same steps as described in Preparation Example 26. Example 31:

將在MeOH、1，2-二甲氧基乙烷及H2〇中來自製備實例的產 物（1當量）與碳酸鉀（10當量）之混合物在5〇χ：ιΝ2下授掉2小 時接著加入CH2C12 ’將混合物經NaJO4乾燥及過減。將溶 劑蒸發，並將殘餘物在以EtOAc/MeOH之矽膠上的管柱色層 87870 -39- 200412967 分離法純化，產生純產物。 實例32-35 :A mixture of the product from the preparation example (1 eq.) And potassium carbonate (10 eq.) In MeOH, 1,2-dimethoxyethane and H2O was decanted for 2 hours at 50 × 2n2 followed by the addition of CH2C12 'Dry the mixture over NaJO4 and reduce it. The solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc / MeOH 87870 -39- 200412967 to give pure product. Examples 32-35:

與製備實例31所述基本上相同的步騾製備這些化合物。 檢定作用:可如以下所述進行本發明化合物的檢定作用。 桿狀病毒建構法：將週期素A及E以PCR選殖成pVL1393(加 州拉后拉（La Jolla)之Pharmingen)，在胺基末端加入5個組胺酸 殘基，允許在鎳樹脂上的純化作用。表現蛋白質具有約46 kDa(週期素E)及50 kDa(週期素A)之尺寸。將CDK2以PCR選 殖成PVL1393，在羧基末端加入血球凝集素抗原決定部位標 籤（YDVPDYAS)。表現蛋白質具有約34 kDa之尺寸。 酵素生產法:將表現週期素A、E與CDK2之重組體桿狀病 毒以相同的多重感染劑量（M〇I=5)經48小時共同感染成SF9 細胞。在1000 RPM下以離心10分鐘收成細胞，接著將細胞片 在冰上經30分鐘溶解在5倍細胞片體積的溶胞緩衝液中（該 緩衝液包括50毫克分子量THs pH 8.0、150毫克分子量NaQ、1% 87870 -40- 200412967 NP40、1毫克分子量DTT及蛋白酶抑制劑（德國曼海姆（Mannheim) 之 Roche Diagnostics GmbH))。將溶胞液在 15000 RPM 下旋轉 10 分 鐘，並保留上澄液。將5毫升鎳珠在溶胞緩衝液中（德國奇 爾根（Qiagen)GmbH)清洗3次（對1公升SF9細胞而言）。將咪唑 加入桿狀病毒上澄液中，成為20毫克分子之最終濃度，接 著與鎳珠在4°C下培育45分鐘。將蛋白質以包括250毫克分子 量咪。坐之溶胞緩衝液溶離。將溶離液在包括50毫克分子量 Tris pH 8.0、1毫克分子量DTT、10毫克分子量MgCl2、100微克 分子量原鈒酸鈉及20%甘油的2公升激酶緩衝液中經隔夜透 析。將酵素整份貯存在-70°C下。 在活體外的激酶檢定：在以低蛋白質結合之96井平盤（紐 約寇尼（Coming)之寇尼公司）中進行CDK2激酶檢定（或週期素 A或E-依賴性）。將酵素在包括50毫克分子量Tris pH 8.0、10毫 克分子量MgCl2、1毫克分子量DTT及0.1毫克分子量原釩酸鈉 之激酶緩衝液中稀釋成50微克/毫升之最終濃度。在這些反 應中所使用的基質係衍生自抗組蛋白抗體Η1(來自英國安莫 山（Amersham))之生物素化肽。將基質在冰上解;東及在激酶 緩衝液中稀釋成2微克分子量。將化合物在10% DMSO中稀 釋成預期濃度。對每一種激酶反應而言，將20微升之50微 克/毫升酵素溶液（1微克酵素）與20微升之2微克分子量基質 溶液混合，接著與在每一個井中的10微升稀釋化合物合併 ，以供測試。以加入50微升之2微克分子量ATP及0.1 μα之 33Ρ-ΑΤΡ(來自英國安莫山）開始激酶反應。允許反應在室溫 下進行1小時。以加入包括0.1% Triton Χ-100、1毫克分子量ΑΤΡ 87870 -41 - 200412967 、5毫克分子EDTA及5毫克/毫升以抗生蛋白鏈菌素塗佈之 SPA珠（來自英國安莫山）之200微升終止緩衝液經15分鐘終止 反應。接著使用Filtermate萬能的捕獲器（帕卡德/鉑金艾爾默 生物科技（Packard/Perkin Elmer Life Sciences))將 SPA珠捕獲在 96-井GF/B過濾盤上（帕卡德/鉑金艾爾默生物科技）。以2克分 子量NaCl清洗珠兩次及接著以具有1%磷酸之2克分子量NaCl 清洗珠兩次，以消除非特異性信號。接著使用TopCount 96井 液體閃爍計數器（來自帕卡德/鉑金艾爾默生物科技）測量放 射活性信號。 1^50測定:自每次重複的8點連續的抑制化合物稀釋劑產 生的抑制數據作出劑量反應曲線圖。以化合物濃度對以未 治療之樣品的CPM除以治療之樣品的CPM計算的激酶活性％ 作圖。為了產生IC5〇值（使用上述檢定的週期素A或週期素E) ，接著將劑量反應曲線配合標準的S型曲線，並以非線性回 歸分析得到IC5Q值。 雖然已連同以上所述特殊的具體實施例說明本發明，但 是那些一般熟悉本技藝的人會明白許多其替換實例、修改 實例及其它變化實例。計劃將所有的這些替換實例、修改 實例及變化實例落在本發明的精神及範圍内。 87870 -42-These compounds were prepared in substantially the same steps as described in Preparation Example 31. Verification effect: The verification effect of the compound of the present invention can be performed as described below. Baculovirus construction method: Cyclin A and E were cloned into pVL1393 (Pharmingen of La Jolla, California) by PCR, and 5 histidine residues were added to the amine end, allowing the Purification. The expressed protein has a size of approximately 46 kDa (cyclin E) and 50 kDa (cyclin A). CDK2 was cloned into PVL1393 by PCR, and a hemagglutinin epitope tag (YDVPDYAS) was added to the carboxyl terminus. The expressed protein has a size of about 34 kDa. Enzyme production method: Recombinant baculoviruses expressing cyclin A, E and CDK2 were co-infected into SF9 cells at the same multiple infectious dose (MOI = 5) over 48 hours. Cells were harvested by centrifugation at 1000 RPM for 10 minutes, and then the cell sheet was dissolved on ice for 5 minutes in a lysis buffer of 5 times the cell sheet volume (the buffer includes 50 mg molecular weight THs pH 8.0, 150 mg molecular weight NaQ , 1% 87870 -40- 200412967 NP40, 1 mg molecular weight DTT and protease inhibitor (Roche Diagnostics GmbH, Mannheim, Germany). Spin the lysate at 15000 RPM for 10 minutes and retain the supernatant. Wash 5 ml of nickel beads in lysis buffer (Qiagen GmbH, Germany) 3 times (for 1 liter of SF9 cells). Imidazole was added to the baculovirus supernatant to a final concentration of 20 mg molecules, followed by incubation with nickel beads at 4 ° C for 45 minutes. Protein was included to include 250 milligrams of molecular weight. The sitting lysis buffer was lysed. The eluate was dialyzed overnight in a 2 liter kinase buffer comprising 50 mg of molecular weight Tris pH 8.0, 1 mg of molecular weight DTT, 10 mg of molecular weight MgCl2, 100 µg of molecular weight sodium orthosulfate, and 20% glycerol. Store the entire enzyme at -70 ° C. Kinase assay in vitro: CDK2 kinase assay (or cyclin A or E-dependent) in a 96-well plate (Coming's Coney) with low protein binding. The enzyme was diluted to a final concentration of 50 μg / ml in a kinase buffer comprising 50 mg Tris pH 8.0, 10 mg MgCl2, 1 mg DTT and 0.1 mg sodium orthovanadate. The matrix used in these reactions was derived from a biotinylated peptide of anti-histone antibody Η1 (from Amersham, UK). Dissolve the matrix on ice; dilute to 2 μg molecular weight in kinase buffer. The compound was diluted to the expected concentration in 10% DMSO. For each kinase reaction, 20 μl of a 50 μg / ml enzyme solution (1 μg of enzyme) was mixed with 20 μl of a 2 μg molecular weight matrix solution, and then combined with 10 μl of the diluted compound in each well, For testing. The kinase reaction was started by adding 50 μl of 2 μg molecular weight ATP and 0.1 μα of 33P-ATP (from Mount Amo, UK). The reaction was allowed to proceed at room temperature for 1 hour. 200 μl of 0.1% Triton X-100, 1 mg molecular weight ATP 87870 -41-200412967, 5 mg molecular EDTA, and 5 mg / ml SPA beads (from Mount Amo, UK) coated with streptavidin The stop buffer was terminated in 15 minutes. The SPA beads were then captured on a 96-well GF / B filter disc (Packard / Platinum Elmer Life Sciences) using a Filtermate universal catcher (Packard / Perkin Elmer Life Sciences) Biological Technology). The beads were washed twice with 2 g molecular weight NaCl and then washed twice with 2 g molecular weight NaCl with 1% phosphoric acid to eliminate non-specific signals. The TopCount 96 well liquid scintillation counter (from Packard / Platinum Elmer Biotechnology) was then used to measure the radioactive signal. 1 ^ 50 determination: A dose-response curve is generated from the inhibition data generated by 8 consecutive points of inhibitor compound diluent in each repetition. Compound concentration is plotted against% kinase activity calculated as the CPM of the untreated sample divided by the CPM of the treated sample. In order to generate the IC50 value (using the above-mentioned cyclin A or cyclin E), the dose-response curve was matched with a standard S-shaped curve, and the IC5Q value was obtained by nonlinear regression analysis. Although the present invention has been described in conjunction with the specific embodiments described above, those skilled in the art will appreciate many alternatives, modifications, and other variations. It is intended that all such alternatives, modifications, and variations fall within the spirit and scope of the present invention. 87870 -42-

Claims (1)

200412967 拾、申請專利範圍· 1. 一種以結構式代表的化合物200412967 Patent application scope 1. A compound represented by the structural formula r3，,n、h 式III 其中： R係選自由燒基、CF3、雜芳基、雜芳境基、環燒基、環 烷基烷基、雜環基、雜環烷基、芳燒某、、r3,, n, h Formula III wherein: R is selected from the group consisting of alkyl, CF3, heteroaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aromatic ,, 所組成的群組’其中每一個該燒基、雜芳基、芳燒其、 環烷基、雜環基及雜環基部份其結構係如以上剛以R所示 者可以未經取代或視需要獨乂以' 或多個可以相同或不 相同的部份取代，每一部份係獨立選自由鹵素、烷基、 環烷基、CF3、CN、-〇CF3、-OR6、-C(0)R7、-NR5R6、_c(〇2)R6、 -C(〇)NR5R6、-(CHR5)nOR6、-SR6、-S(〇2)R7、-S(02)NR5R6、-N(R5)S(〇2)R7 、-n(r5)c(o)r7 及-n(r5)c(〇)nr5r6所組成的群組； R1係Η、画素或烷基； R2係選自由Η、||素、CN、環烷基、雜環基、炔基及 -CF3所組成的群組； 87870 200412967 R3係選自.由芳基（除了苯基之外）、雜芳基（除了呋喃基 之外）、雜環基、-(CHRV雜芳基、-S(〇2)R6、-C(0)R6、 -(CHR5)n—N-\ -s(o2)nr5r6、-c(o)〇R6、-c(o)nr5r6、 〇以’、 •(CHR5〉n—N厂Vr8 V"(CH2)m^~VR8 N一/ ，及 \一7 所組成的群組，其中每 一個該芳基、雜芳基及雜環基可以未經取代或視需要以 一或多個可以相同或不相同的部份取代，每一部份係獨The group 'each of which is an alkyl group, a heteroaryl group, a aryl group, a cycloalkyl group, a heterocyclic group, and a heterocyclic moiety whose structures are as shown above and may be unsubstituted or If necessary, it may be substituted with 'or more moieties which may be the same or different, each of which is independently selected from halogen, alkyl, cycloalkyl, CF3, CN, -〇CF3, -OR6, -C ( 0) R7, -NR5R6, _c (〇2) R6, -C (〇) NR5R6,-(CHR5) nOR6, -SR6, -S (〇2) R7, -S (02) NR5R6, -N (R5) S (〇2) R7, -n (r5) c (o) r7 and -n (r5) c (〇) nr5r6; R1 is Η, pixel or alkyl; R2 is selected from Η, | | Group consisting of prime, CN, cycloalkyl, heterocyclyl, alkynyl and -CF3; 87870 200412967 R3 is selected from the group consisting of aryl (other than phenyl), heteroaryl (other than furanyl) Outer), heterocyclyl,-(CHRV heteroaryl, -S (〇2) R6, -C (0) R6,-(CHR5) n-N-\-s (o2) nr5r6, -c (o) 〇R6, -c (o) nr5r6, 〇 ', • (CHR5> n—N Factory Vr8 V " (CH2) m ^ ~ VR8 N_ /, and \ -7, each of which should Aryl, heteroaryl and heterocyclyl may be Substituted or optionally replaced with one or more parts which may be the same or different, each part being independent 立選自由鹵素、烷基、芳基、環烷基、CF3、CN、-OCF3、 -OR’、-NR’R6、-C(02)R5、-C(0)NR5R6、-SR6、-S(02)R6、-S(02)NR5R6 、-n(r5)s(o2)r7、-n(r5)c(o)r7 及-n(r5)c(o)nr5r6 所組成的群組 ，其先決條件係當R3係-(CHR5)njg芳基時，則R2可以另外 係燒基； R5係Η或烷基；Li is selected from halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, -OR ', -NR'R6, -C (02) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -n (r5) s (o2) r7, -n (r5) c (o) r7, and -n (r5) c (o) nr5r6, The prerequisite is that when R3 is-(CHR5) njg aryl, then R2 may be another alkyl; R5 is fluorene or alkyl; R6係選自由Η、烷基、芳基、雜芳基、芳烷基及雜芳烷 基所組成的群組，其中每一個該烷基、雜芳烷基、芳基 、雜芳基及芳烷基可以未經取代或視需要以一或多個可 以相同或不相同的部份取代，每一部份係獨立選自由鹵 素 '烷基、芳基、環烷基、CF3、OCF3、CN、-OR5、-NR5R6、 -CH2OR5 > -C(02)R5 > -C(0)NR5R6 ^ -SR6 ^ -S(02)R7 ' -S(02)NR5R6 ' -n(r5)s(o2)r7、-N(R5)C(0)R7 及-N(R5)C(0)NR5R6 所組成的群組； R7係選自由烷基、芳基、雜芳基、芳烷基及雜芳烷基 所組成的群組，其中每一個該烷基、雜芳烷基、芳基、 雜芳基及芳烷基可以未經取代或視需要以一或多個可以 相同或不相同的部份取代，每一部份係獨立選自由鹵素 87870 200412967 、烷基、芳基、環烷基、CF3、OCF3、CN、-OR5、-NR5R6、 -CH2〇R5、-C(02)R5、-C(0)NR5R6、-SR6、-S(〇2)R7、-S(〇2)NR5R6、 -N(R5)S(〇2)R7、-N(R5)C(〇)R7 及-N(R5)C(〇)NR5R6 所組成的群組； R8 係選自由 R6、-C(〇)NR5R6、-S(〇2)NR5R6、-C(〇)R7、-C(〇2)R6 、-s(o2)r7及-(ch2)-芳基所組成的群組； m係0至4 ;及 η 係 1-4。 2.根據申請專利範圍第1項之化合物，其中R係選自由烷基 、雜芳烷基、環烷基、環烷基烷基、雜環基、雜環烷基 、芳垸基、R6 is selected from the group consisting of fluorene, alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is alkyl, heteroaralkyl, aryl, heteroaryl, and aryl The alkyl group may be unsubstituted or substituted with one or more moieties which may be the same or different, and each moiety is independently selected from the group consisting of halogen 'alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -CH2OR5 > -C (02) R5 > -C (0) NR5R6 ^ -SR6 ^ -S (02) R7 '-S (02) NR5R6' -n (r5) s (o2 ) r7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R7 is selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl and heteroaryl A group of alkyl groups, where each of the alkyl, heteroaralkyl, aryl, heteroaryl, and aralkyl groups may be unsubstituted or, if necessary, one or more parts that may be the same or different Substitution, each part is independently selected from halogen 87870 200412967, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -CH2OR5, -C (02) R5, -C (0) NR5R6, -SR6, -S (〇2) R7, -S (〇2) NR5R6, -N (R5) S (〇2) R7, -N (R5) C (〇) R7, and -N ( R5) C (〇) NR 5R6; R8 is selected from the group consisting of R6, -C (〇) NR5R6, -S (〇2) NR5R6, -C (〇) R7, -C (〇2) R6, -s (o2) r7 and a group consisting of-(ch2) -aryl; m is 0 to 4; and η is 1-4. 2. The compound according to item 1 of the scope of patent application, wherein R is selected from the group consisting of alkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, arylfluorenyl, 所組成的群組，其中以上R所示之每一個該烷基、雜芳基 、環烷基、芳烷基、雜環基及雜環基部份可以未經取代 或視需要獨立以一或多個可以相同或不相同的部份取代 ，每一部份係獨立選自由鹵素、烷基、環烷基、CF3、CN 、-OCF3、-OR6、-C(0)R7、-NR5R6、-C(02)R6、-C(〇)NR5R6、-SR6、 -s(o2)r7、-S(02)NR5R6、-N(R5)S(02)R7、-N(R5)C(0)R7 及-n(r5)c(o)nr5r6 所組成的群組； R1係H或幽素； 87870 2〇〇412967 R2係選自·由Η、鹵素、環烷基、CN、炔基及_Cf3所組成 的群組； R3係選自由芳基、雜芳基、雜環基、-(CHR5)n-雜芳基、 -S(02)R6 ^ -C(0)R6 ^ -S(〇2)NR5R6 > -C(0)〇R6 > -C(0)NR5R6 > 仰 R5)nA group consisting of each of the alkyl, heteroaryl, cycloalkyl, aralkyl, heterocyclyl, and heterocyclyl moieties shown by R above may be unsubstituted or independently Multiple may be substituted with the same or different parts, each part is independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF3, CN, -OCF3, -OR6, -C (0) R7, -NR5R6,- C (02) R6, -C (〇) NR5R6, -SR6, -s (o2) r7, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) Group consisting of R7 and -n (r5) c (o) nr5r6; R1 is H or peptin; 87870 2〇412967 R2 is selected from the group consisting of Η, halogen, cycloalkyl, CN, alkynyl and _ The group consisting of Cf3; R3 is selected from the group consisting of aryl, heteroaryl, heterocyclyl,-(CHR5) n-heteroaryl, -S (02) R6 ^ -C (0) R6 ^ -S (〇 2) NR5R6 > -C (0) 〇R6 > -C (0) NR5R6 > Yang R5) n -(CHR5)n一N N-R8 S/(CH2)m^N_R8 所組成的 群組，其中每一個該芳基、雜芳基及雜環基可以未經取 代或視需要以一或多個可以相同或不相同的部份取代， 每一部份係獨立選自由鹵素、烷基、芳基、環烷基、cf3 、cn、-ocf3、-n(r5)c(o)r7、-c(o)nr5r6、-s(02)r5及-n(r5)c(0)r7 所組成的群組； R5係Η或低碳烷基； m係〇至2 ;及 η係1至3。 3 •根據申請專利範圍第2項之化合物，其中R係燒基、芳：]：完 基或環烷基烷基。 4·根據申請專利範圍第3項之化合物，其中R係選自由甲基 '乙基、三級-丁基、環己基甲基、芊基及苯乙基所組成 的群組。 5·根據申請專利範圍第2項之化合物，其中R1係Η。 6 •根據申請專利範圍第2項之化合物，其中R1係甲基。 7 •根據申請專利範圍第2項之化合物，其中R2係Η、F、C1、 Br 或 I。 8 j. • R據申請專利範圍第7項之化合物，其中R2係Br。 據申凊專利範圍第8項之化合物，其中R3係（υ比淀-2 -基） 87870 -4- ZUU412967 10. 11. 12. 13. 14. 15. 甲基、0比.咬-3-基）甲基、（吡啶_4_基）甲基、嘧嗯-2-基或 口塞 口風-Λ λΛ. ^ -卷’其中該吡啶基及ρ塞嗯基可以未經取代或視需 要獨立W 一 斗、々 、 Λ 一或夕個可以相同或不相同的部份取代，每一 沣6係獨立選自由F、α、Br、cf3、低碳烷基、甲氧基及 CNm組成的群組。 根據申請專利範圍第9項之化合物，其中R3係（吡啶_2_基） 甲基。 根據申清專利範圍第9項之化合物，其中R3係（吡啶-3-基） 甲基。 根據申清專利範圍第9項之化合物，其中R3係（吡啶基） 甲基。 根據申請專利範圍第2項之化合物，其中㈤係〇。 根據申請專利範圍第2項之化合物，其中11係1。 一種如下式之化合物：-(CHR5) n-N N-R8 S / (CH2) m ^ N_R8, wherein each of the aryl, heteroaryl, and heterocyclic groups may be unsubstituted or one or more as needed It may be substituted with the same or different parts, and each part is independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cf3, cn, -ocf3, -n (r5) c (o) r7, -c (o) a group consisting of nr5r6, -s (02) r5, and -n (r5) c (0) r7; R5 is fluorene or lower alkyl; m is 0 to 2; and η is 1 to 3. 3 • The compound according to item 2 of the scope of patent application, in which R is an alkyl group, an aryl group:]: an end group or a cycloalkylalkyl group. 4. The compound according to item 3 of the application, wherein R is selected from the group consisting of methyl'ethyl, tertiary-butyl, cyclohexylmethyl, fluorenyl, and phenethyl. 5. The compound according to item 2 of the scope of patent application, wherein R1 is fluorene. 6 • The compound according to item 2 of the scope of patent application, wherein R1 is methyl. 7 • The compound according to item 2 of the scope of patent application, wherein R2 is Η, F, C1, Br or I. 8 j. • Compound according to item 7 of the scope of patent application, wherein R2 is Br. According to the application of the eighth patent scope of the compound, in which R3 (υ Bidian-2-based) 87870 -4- ZUU412967 10. 11. 12. 13. 14. 15. Methyl, 0 ratio. Bite -3- Group) methyl, (pyridine_4_yl) methyl, pyrim-2-yl or mouth-mouth tone-Λ λ Λ. ^-Vol. 'Wherein the pyridyl and ρ ceryl can be unsubstituted or as needed Independent W Yidou, 々, Λ can be replaced by the same or different parts, each 沣 6 is independently selected from the group consisting of F, α, Br, cf3, lower alkyl, methoxy and CNm Group. The compound according to item 9 of the scope of patent application, wherein R3 is (pyridine_2_yl) methyl. The compound according to item 9 of the Shen Qing patent, wherein R3 is (pyridin-3-yl) methyl. The compound according to item 9 of the patent application, wherein R3 is (pyridyl) methyl. The compound according to item 2 of the patent application, wherein ㈤ is 0. The compound according to item 2 of the patent application scope, in which 11 is 1. A compound of the formula: 87870 20041296787870 200412967 請專利範圍第1項之化合物與至少一 載體。 剛I的至少一種如申 種在醫藥上可接受之 種用於治療一或多種與週期素依 病的醫藥組合物，其包含有效治療 其中該週期素 根據申請專利範圍第17項之醫藥組合物 依賴性激酶係CDK2。 19·根據申請專利範圍第17項之醫藥組合物，其中該週期素 依賴性激酶係以促細胞***劑活化之蛋白激酶(MApK/ERK)。 20·根據申請專利範圍第17項之醫藥組合物，其中該週期素 依賴性激酶係糖原合成酶激酶3 (GSK3p)。 21·根據申請專利範圍第17項之醫藥組合物，其中該疾病係 選自由以下所組成之群： 膀胱癌、乳癌、直腸癌、腎癌、肝癌、肺癌、非小細 胞肺癌、食道癌、膽囊癌、卵巢癌、胰臟癌、胃癌、子 言頸癌、甲狀腺癌、攝護腺癌及皮膚癌（包括鱗狀細胞 瘤）； 白血病、急性淋巴細胞性白血病、急性淋巴性白血病 、B -細胞淋巴瘤、T-細胞淋巴瘤、何杰金氏淋巴瘤、非 何杰金氏淋巴瘤、髮狀細胞淋巴瘤及巴奇氏惡性淋巴瘤； 急性和慢性骨髓性白血病、骨髓發育不良徵候群及前 87870 -6- 200412967 骨髓細胞白血病； 纖維肉瘤及橫紋肌肉瘤； 星狀細胞瘤、神經細胞瘤、神經膠質瘤及神經鞘瘤，· 黑色素細胞瘤、***細胞瘤、畸胎瘤、骨瘤、著色性 乾皮病、角化棘皮瘤、甲狀腺濾泡癌及卡波西氏肉瘤。 22· —種用於治療一或多種與週期素依賴性激酶有關連之疾 病的醫藥組合，其包含 、 第一種化合物之劑量，其係一種如申請專利範圍第i項 之化合物或其在醫藥上可接受之鹽或媒合物；及 至少一個第二種化合物之劑量，該第二種化合物係抗 癌劑； 其中以第一種化合物及該第二種化合物之劑量得到療 效。 23·根據申請專利範圍第22項之醫藥組合，其進一步包含照 射治療法。 根據申請專利範圍第22項之醫藥組合，纟中該抗癌劑係 選自由細胞抑制劑、順氯氨鉑、阿霉素、剋癌.易、紅豆 杉醇、順鉑、CPT-11、伊利替康、刊普托斯塔、托波替康 、紫杉醇、歐洲紫杉醇、埃波霉素、三苯氧胺、5_氟尿 嘴咬、氨甲蝶呤、5FU、帝蒙柔羅麥德、環磷醯胺、SCH 66336、R115777、l778，123、214662、艾瑞沙、塔西伐、 EGFR的抗體、格里維克、内含子、、亞德里亞霉素 、裱磷醯胺、吉西它賓、尿嘧啶氮芥、氮芥、異環磷醯 胺、美法蘭、苯丁酸氮芥、皮波伯曼、三乙撐蜜胺、三 87870 200412967 乙撐硫代磷酸醯胺、白消安、卡幕司他汀、路幕司他汀 、鏈脲佐菌素、達卡巴阱、氟脫氧尿苷、阿糖胞苷、6_ 硫基嘌呤、6-硫代鳥嘌呤、氟達拉賓磷酸鹽、奥沙利鉑 、琉可維瑞、eloxatin™、潘托司他汀、長春花鹼、長 春新鹼、長春地辛、博菜霉素、放線霉素、道諾紅菌素 、阿霉素、表阿霉素、伊達比辛、光神霉素、脫氧肋間 型霉素、絲裂霉素-C、L-天冬醯胺酶、替尼泊苷17(χ•炔 ***、二乙基己烯雌酚、睪酮、脫氫可的松、氟甲睪 酮、拓莫斯丹諾酮丙酸鹽、睪内酯、甲地孕酮醋酸鹽、 甲基脫氫皮醇、甲基睪酮、脫氫皮醇、氫羥脫氫皮醇、 氯烯雌醚、羥基孕激素、胺格魯米德、雌莫司汀、甲孕 酮醋酸鹽、琉普利德、氟塔麥德、托瑞米芬、固色林、 順氯氨鉑、卡鉑、羥基脲、安吖啶、普卡巴阱、米托坦 、米托杉酮、左美素、納維賓、CPT_U、安納退唑、來退 唑、凱普西塔賓、瑞羅杉芬、拓羅山芬或六甲基蜜胺所 組成的群組。 25. 26. 一種醫藥組合物，其包含有效治療劑量的至少一種如申 請專利範圍第i項之化合物與至少一種在醫藥上可接為 載體。 又 根據申請專利範圍第25項之醫藥組合物，其另外包含一 或多種選自由細胞抑制劑、順氯氨鉑、、阿 、紅豆杉醇、順銘、CPT-n、伊利替康、刊普托斯塔:托 波替康、紫杉醇、歐洲紫杉醇、埃波霉素、三苯氧胺、 5-氟尿‘定、氨甲蝶呤、5FU、帝蒙柔羅麥德、環鱗臨 87870 200412967 胺）、SCH 66336、、R115777、L778，123、BMS 214662、艾瑞沙 、塔西伐、EGFR的抗體、格里維克、内含子、ara-C、亞 德里亞霉素、環鱗醯胺、吉西它賓、尿嘧啶氮芥、氮芥 '異環磷醯胺、美法蘭、苯丁酸氮芥、皮波伯曼、三乙 撐蜜胺、三乙撐硫代磷酸醯胺、白消安、卡幕司他汀、 路幕司他汀、鏈脲佐菌素、達卡巴阱、氟脫氧尿苷、阿 糖胞苷、6-豉基嘌呤、6-硫代烏嘌呤、氟達拉賓磷酸鹽 、潘托司他汀、長春花鹼、長春新鹼、長春地辛、博莱 霉素、放線霉素、道諾紅菌素、阿霉素、表阿霉素、伊 達比辛、光神霉素、脫氧肋間型霉素、絲裂霉素<、L_ 天冬醯胺酶、替尼泊：y： 17心炔***、二乙基己烯雌酚、 睪酮、脫氫可的松、氟甲睪酮、拓莫斯丹諾酮丙酸鹽、 睪内酯、甲地孕酮醋酸鹽、甲基脫氩皮醇、甲基睪酮、 脫氫皮s予、氫！脫氫皮醇、氯烯雌醚、羥基孕激素、胺 格魯米德、雌莫司汀、甲孕酮醋酸鹽、琉普利德、氟塔 “心托奂米务、固色林、順氯氨鉑、卡鉑、羥基脲、 日卡巴陈、米托坦、米托杉嗣、左美素、納維 賓CPT 11 *納退味、來退唆、訊普西塔賓、瑞羅杉芬 、拓羅山芬或六甲基蜜胺所組成的群組之抗癌劑。 27. 種、屯化土式的如申凊專利範圍第i項之化合物。 87870 200412967 柒、指定代表圖： (一) 本案指定代表圖為：（無）。 (二) 本代表圖之元件代表符號簡單說明： 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：The compound in item 1 of the patent is requested with at least one carrier. At least one of the pharmaceutical compositions acceptable for treating one or more cyclin-dependent diseases as claimed in claim 1 comprises a pharmaceutical composition effective for treating the cyclin according to item 17 of the scope of patent application CDK2. 19. The pharmaceutical composition according to item 17 of the application, wherein the cyclin-dependent kinase is a protein kinase (MApK / ERK) activated by a mitogen. 20. The pharmaceutical composition according to item 17 of the scope of patent application, wherein the cyclin-dependent kinase is glycogen synthase kinase 3 (GSK3p). 21. The pharmaceutical composition according to item 17 of the scope of the patent application, wherein the disease is selected from the group consisting of bladder cancer, breast cancer, rectal cancer, kidney cancer, liver cancer, lung cancer, non-small cell lung cancer, esophageal cancer, gallbladder Cancer, ovarian cancer, pancreatic cancer, gastric cancer, zodiac cancer, thyroid cancer, prostate cancer and skin cancer (including squamous cell tumors); leukemia, acute lymphocytic leukemia, acute lymphocytic leukemia, B-cells Lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Badge's malignant lymphoma; acute and chronic myeloid leukemia, myelodysplastic syndromes, and Pre 87870 -6- 200412967 Myeloid cell leukemia; Fibrosarcoma and rhabdomyosarcoma; Stellate cell tumor, neuroblastoma, glioma, and schwannoma, · Melanoma, spermatoma, teratoma, osteoma, Xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma. 22 · —A pharmaceutical combination for treating one or more diseases related to cyclin-dependent kinases, comprising a dose of the first compound, which is a compound such as the item i of the patent application scope or its medicinal use An acceptable salt or vehicle; and a dose of at least one second compound, the second compound being an anticancer agent; wherein the therapeutic effect is obtained with the dose of the first compound and the second compound. 23. The pharmaceutical combination according to item 22 of the scope of patent application, which further comprises a radiation therapy method. According to the pharmaceutical composition under the scope of application patent No. 22, the anticancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, and cancer. Yi, taxol, cisplatin, CPT-11, Yili Ticonazole, Protopa, Topotecan, Paclitaxel, Paclitaxel, Epothilone, Tamoxifen, 5-Fluorine Mouth Bites, Methotrexate, 5FU, Dimonolomade, Cyclophosphate Amines, SCH 66336, R115777, l778, 123, 214662, arisa, taciva, EGFR antibodies, Glik, introns, Adriaticin, Phosphamide, Gemcitabine , Uracil nitrogen mustard, nitrogen mustard, ifosfamide, melphalan, phenylbutyrate mustard, Piebberman, triethylene melamine, three 87870 200412967 ethylene phosphorothioate, busulan Carbestatin, lumonastatin, streptozotocin, dacarbabarine, fluorodeoxyuridine, cytarabine, 6-thiopurine, 6-thioguanine, fludarabine phosphate, Oxaliplatin, luciferide, eloxatin ™, pantostatin, vinblastine, vincristine, vincristine, bleomycin, actinomyces , Daunorubicin, doxorubicin, epirubicin, idabisin, mithromycin, deoxycostinomycin, mitomycin-C, L-asparaginase, teniposide 17 (χ • ethinylestradiol, diethyldiethylstilbestrol, fluorenone, dehydrocortisone, flumethanone, tromstanone propionate, galactone, megestrol acetate, methyldehydro Hydrocortisol, methylphenidone, dehydrocortisol, hydroxydehydrocortisol, chlorestrol, hydroxyprogestin, amine glumide, estramustine, medroxyprogesterone acetate, leuprid , Flutamed, toremifene, fixerlin, cisplatin, carboplatin, hydroxyurea, anacridine, procarbazone, mitotan, mitotaxone, levmeme, neravibin , CPT_U, anastrozole, letrozole, capecitabine, raloxan, toloxacin, or hexamethylmelamine. 25. 26. A pharmaceutical composition comprising an effective therapeutic dose At least one of the compound as claimed in the scope of patent application i and at least one pharmaceutically acceptable carrier. Also according to the pharmaceutical composition as claimed in scope 25 of the patent application , Which additionally comprises one or more selected from the group consisting of cytostatics, cisplatin, arbotaxel, cisplatin, CPT-n, irinotecan, putostata: topotecan, paclitaxel, Europe Paclitaxel, epothilone, tamoxifen, 5-fluorouridine, methotrexate, 5FU, dimonolomade, cyclosexin 87870 200412967 amine), SCH 66336, R115777, L778, 123, BMS 214662 , Iressa, Taciva, EGFR antibodies, Glick, introns, ara-C, adriamycin, cyclostigmine, gemcitabine, uracil nitrogen mustard, nitrogen mustard ' Ifosfamide, melphalan, chlorambucil, pipberman, triethylenemelamine, triethylphosphonium phosphorothioate, busulfan, carmusstatin, lumonastatin, Streptozotocin, dacarbazine, fludeoxyuridine, cytarabine, 6-amidinopurine, 6-thiouranine, fludarabine phosphate, pantostatin, vinblastine, vinblastine Nematine, Vindesine, Bleomycin, Actinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idabisin, Photomycetin, Deoxyintercostal Mycin, mitomycin <, L_aspartase, tenipoise: y: 17-ethynyl estradiol, diethyl diethylstilbestrol, fluorenone, dehydrocortisone, flumethenone, tomus Tannone propionate, galactone, megestrol acetate, methyldehydrocortisol, methylacetophenone, dehydrocorticosterone, hydrogen! Dehydrocortisol, chlorestradiol, hydroxyprogesterone, amine glumide, estramustine, megestrol acetate, Ryprid, Fluta Cisplatin, carboplatin, hydroxyurea, carbabacin, mitotan, mitotaxel, levmeme, navidin CPT 11 Anti-cancer agents in the group consisting of Taluoshanfen or Hexamethylmelamine. 27. Compounds of item i in the scope of the patent of Rushen Patent, 87870 200412967 柒, designated representative map: (a ) The designated representative figure in this case is: (none). (2) Brief description of the element representative symbols in this representative figure: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 8787087870
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Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001124A1 (en) * 1996-12-03 1999-01-14 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US20020058286A1 (en) * 1999-02-24 2002-05-16 Danishefsky Samuel J. Synthesis of epothilones, intermediates thereto and analogues thereof
CA2482991A1 (en) 2002-04-19 2003-10-30 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines method of making and method of use thereof
US7649006B2 (en) * 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
AU2003260002B2 (en) 2002-08-23 2010-03-18 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
WO2004022562A1 (en) * 2002-09-09 2004-03-18 Cellular Genomics, Inc. 6-ARYL-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINES, METHOD OF MAKING, AND METHOD OF USE THEREOF
US7576085B2 (en) * 2002-09-23 2009-08-18 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
NZ538685A (en) * 2002-09-23 2008-02-29 Schering Corp Imidazopyrazines as cyclin dependent kinase inhibitors
WO2004072081A1 (en) * 2003-02-10 2004-08-26 Cellular Genomics, Inc. Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of kinase activity
US20060183746A1 (en) * 2003-06-04 2006-08-17 Currie Kevin S Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
US7405295B2 (en) * 2003-06-04 2008-07-29 Cgi Pharmaceuticals, Inc. Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
US7393848B2 (en) 2003-06-30 2008-07-01 Cgi Pharmaceuticals, Inc. Certain heterocyclic substituted imidazo[1,2-A]pyrazin-8-ylamines and methods of inhibition of Bruton's tyrosine kinase by such compounds
WO2005019220A2 (en) * 2003-08-11 2005-03-03 Cellular Genomics Inc. Substituted imidazo[1,2-a]pyrazines as modulators of kinase activity
WO2005085252A1 (en) * 2004-03-04 2005-09-15 Biofocus Discovery Limited Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases
CN102267978A (en) * 2005-01-14 2011-12-07 Cgi药学股份有限公司 1,3-diaryl substituted ureas as modulators of kinase activity
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
TW200800213A (en) 2005-09-02 2008-01-01 Abbott Lab Novel imidazo based heterocycles
CA2621983A1 (en) * 2005-09-09 2007-03-22 Schering Corporation Azafused cyclin dependent kinase inhibitors
CA2622867A1 (en) * 2005-09-16 2007-03-22 Schering Corporation Pharmaceutical compositions and methods using temozolomide and a protein kinase inhibitor
WO2007056468A1 (en) 2005-11-10 2007-05-18 Schering Corporation Methods for inhibiting protein kinases
AU2006315718B2 (en) * 2005-11-10 2012-10-04 Merck Sharp & Dohme Corp. Imidazopyrazines as protein kinase inhibitors
US20090018142A9 (en) * 2006-05-02 2009-01-15 Zhengping Zhuang Use of phosphatases to treat tumors overexpressing N-CoR
US20090175852A1 (en) 2006-06-06 2009-07-09 Schering Corporation Imidazopyrazines as protein kinase inhibitors
CN103788108B (en) * 2007-02-06 2017-04-12 利克斯特生物技术公司 Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
CA2718472A1 (en) * 2007-08-03 2009-02-12 Lixte Biotechnology, Inc. Use of phosphatases to treat neuroblastomas and medulloblastomas
ES2628748T3 (en) * 2007-10-01 2017-08-03 Lixte Biotechnology, Inc. HDAC inhibitors
AU2009215191A1 (en) 2008-02-13 2009-08-20 Gilead Connecticut, Inc. 6-aryl-imidaz0[l, 2-a] pyrazine derivatives, method of making, and method of use thereof
CA2730428A1 (en) * 2008-08-01 2010-02-04 Lixte Biotechnology, Inc. Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase
US8058268B2 (en) * 2008-08-01 2011-11-15 Lixte Biotechnology, Inc. Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
US8227473B2 (en) * 2008-08-01 2012-07-24 Lixte Biotechnology, Inc. Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
WO2010147612A1 (en) 2009-06-18 2010-12-23 Lixte Biotechnology, Inc. Methods of modulating cell regulation by inhibiting p53
JP5696052B2 (en) 2008-12-08 2015-04-08 ギリアード コネチカット， インコーポレイテッド Imidazopyrazine SYK inhibitor
PT2716157T (en) 2008-12-08 2016-08-23 Gilead Connecticut Inc Imidazopyrazine syk inhibitors
US8450321B2 (en) 2008-12-08 2013-05-28 Gilead Connecticut, Inc. 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor
US8993535B2 (en) 2009-09-04 2015-03-31 Merck Sharp & Dohme Corp. Modulators of cell cycle checkpoints and their use in combination with checkpoint kinase inhibitors
MX2012004990A (en) 2009-10-30 2012-06-12 Janssen Pharmaceutica Nv IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS.
AR080754A1 (en) 2010-03-09 2012-05-09 Janssen Pharmaceutica Nv IMIDAZO DERIVATIVES (1,2-A) PIRAZINA AND ITS USE AS PDE10 INHIBITORS
US9562056B2 (en) 2010-03-11 2017-02-07 Gilead Connecticut, Inc. Imidazopyridines Syk inhibitors
CA2821817A1 (en) * 2010-12-17 2012-06-21 Bayer Intellectual Property Gmbh Substituted 6-imidazopyrazines for use as mps-1 and tkk inhibitors in the treatment of hyperproliferative disorders
JP2013545779A (en) * 2010-12-17 2013-12-26 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 6-substituted imidazopyrazines for use as MPS-1 and TKK inhibitors in the treatment of hyperproliferative disorders
AU2012277912B2 (en) 2011-06-27 2017-03-23 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
AU2013283426B2 (en) 2012-06-26 2018-02-22 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl- [1,2,4] triazolo [4,3-a] quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological or metabolic disorders
CA2875057C (en) 2012-07-09 2021-07-13 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyrazine compounds and their use as inhibitors of the phosphodiesterase 10 enzyme
CA2909160C (en) 2013-04-09 2021-05-25 Lixte Biotechnology, Inc. Formulations of oxabicycloheptanes and oxabicycloheptenes
JP6153667B2 (en) 2013-07-30 2017-06-28 ギリアード コネチカット， インコーポレイテッド Formulation of SKY inhibitor
PL3027618T3 (en) 2013-07-30 2021-04-19 Kronos Bio, Inc. Polymorph of syk inhibitors
SG11201603050TA (en) 2013-12-04 2016-05-30 Gilead Sciences Inc Methods for treating cancers
TWI735853B (en) 2013-12-23 2021-08-11 美商克洛諾斯生技有限公司 Syk inhibitors
US9290505B2 (en) 2013-12-23 2016-03-22 Gilead Sciences, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
MA40075A (en) 2014-07-14 2016-01-21 Gilead Sciences Inc Combinations for treating cancers
US11116755B2 (en) 2015-11-18 2021-09-14 Genzyme Corporation Biomarker of polycystic kidney disease and uses thereof
US11384082B2 (en) 2017-08-25 2022-07-12 Kronos Bio, Inc. Hydrates of polymorphs of 6-(1H-indazol-6-YL)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-A]pyrazin-8-amine bisemsylate as Syk inhibitors
CN113950479A (en) 2019-02-22 2022-01-18 克洛诺斯生物股份有限公司 Solid forms of condensed pyrazines as SYK inhibitors
US20230348475A1 (en) * 2020-09-17 2023-11-02 The Translational Genomics Research Institute Imidazopyridazine and imidazopyrazine compounds as inhibitors of cdk7
CN114042065B (en) * 2021-11-26 2024-03-15 长沙拜特生物科技研究所有限公司 Compound mebendazole transdermal solution and preparation method thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4797764A (en) * 1986-01-27 1989-01-10 Minnesota Mining And Manufacturing Company Recording disk with low total indicated runout
FR2607813B1 (en) 1986-12-05 1989-03-31 Montpellier I Universite ALKYLAMINO-8 IMIDAZO (1,2-A) PYRAZINES AND DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
PT778277E (en) 1995-12-08 2003-11-28 Pfizer HETEROCYCLIC DERIVATIVES SUBSTITUTED AS CRTA ANTAGONISTS
CA2419626A1 (en) 2000-07-14 2002-01-24 Rajagopal Bakthavatachalam Imidazo¬1,2-a|pyrazines for the treatment of neurological disorders
SK18392002A3 (en) 2000-07-26 2003-09-11 Bristol-Myers Squibb Company N-(5-{[(5-alkyl-2-oxazolyl)methyl]thio]-2-thiazolyl} carboxamide inhibitors of cyclin dependent kinases
WO2002060492A1 (en) 2001-01-30 2002-08-08 Cytopia Pty Ltd Methods of inhibiting kinases
CA2482991A1 (en) 2002-04-19 2003-10-30 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines method of making and method of use thereof
NZ538685A (en) * 2002-09-23 2008-02-29 Schering Corp Imidazopyrazines as cyclin dependent kinase inhibitors

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